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TCID	Name	Domain	Kingdom/Phylum	Protein(s)
9.A.14.1.1	Long wave-sensitive opsin (red cone photoreceptor pigment). Phosphorylated on Thr and Ser in the C-terminal region. Defects cause color blindness (protanopia). Catalyzes phospholipid flipping (Menon et al., 2011).	Eukaryota	Metazoa, Chordata	Opsin of Homo sapiens (P04000)
9.A.14.1.2	Rhodopsin. Photoreceptor required for image-forming vision at low light intensity. Light-induced isomerization of 11-cis to all-trans retinal triggers a conformational change leading to G-protein activation and release of all-trans retinal. The tetraspanning peripherin-2 (TC# 8.A.40.1.2) links rhodopsin to a cyclic nucleotide-dependent channel (TC# 1.A.1.5.3) in the outer segments of rod photoreceptors. The G266D retinitis pigmentosa mutation in TMS4 of rhodopsin abolishes binding of peripherin-2 and prevents association with the CNGA1/CNGB1a subunits present in the complex (Becirovic et al. 2014). A channel through opsin, responsible for the passage of retinal from and to its central site where it forms a Schiff's base with a lysine in TMS7 has been proposed (Hildebrand et al. 2009). Blankenship et al. 2015 presented the 2.3-A resolution structure of native source rhodopsin stabilized in a conformation competent for G protein binding. An extensive water-mediated hydrogen bond network linking the chromophore binding site to the site of G protein binding was observed, providing connections to conserved motifs essential for GPCR activation. Both Opsin and Rhodopsin serve as phospholipid flippases (scramblases) and thus have been implicated in photoreceptor disc membrane homeostasis (Menon et al. 2011; Goren et al. 2014; Ernst and Menon 2015; Wang et al. 2018). One particular conformation of rhodopsin is an open channel connecting the ligand binding site with the membrane and the intradiscal lumen of rod outer segments. Sufficient in size, the passageway permits the exchange of hydrophobic ligands such as retinal (Mattle et al. 2018). G protein-coupled receptors such as rhodopsin interact with hydrophobic ligands that probably enter their binding pockets through transmembrane pores (Tian et al. 2022).	Eukaryota	Metazoa, Chordata	Rhodopsin of Homo sapiens (P08100)
9.A.14.1.3	Melatonin receptor type 1A, or MT1 (MR) of 350 aas and 7 TMSs. Although the MT1 and 5-HT receptors have similar endogenous ligands, and agomelatine acts on both receptors, the receptors differ markedly in the structure and composition of their ligand pockets; in MT1, access to the ligand pocket is tightly sealed from solvent by extracellular loop 2, leaving only a narrow channel between transmembrane helices IV and V that connects it to the lipid bilayer (Stauch et al. 2019). The binding site is extremely compact, and ligands interact with MT1 mainly by strong aromatic stacking with Phe179 and auxiliary hydrogen bonds with Asn162 and Gln181. Free-energy simulations support a lipophilic binding route for melatonin receptors (Elisi et al. 2021). Blockage of MRs abolishes its antiarrhythmic effect and slows ventricular conduction in rat hearts (Durkina et al. 2023).	Eukaryota	Metazoa, Chordata	Melatonin receptor type 1A of Homo sapiens (P48039)
9.A.14.1.4	Thyrotropin-releasing hormone receptor	Eukaryota	Metazoa, Chordata	Thyrotropin-releasing hormone receptor of Homo sapiens (P34981)
9.A.14.1.5	Follicle-stimulating hormone receptor	Eukaryota	Metazoa, Chordata	Follicle-stimulating hormone receptor of Homo sapiens (P23945)
9.A.14.1.6	The ghrelin receptor, a peptide-activated (Growth hormone secretagogue) class A GPCR, GHS-R or GH-releasing peptide receptor (Mary et al., 2012). Intestinal dysmotility is associated with decreased ghrelin and vimentin expression and loss of intestinal cells of Cajal (Sukhotnik et al. 2021).	Eukaryota	Metazoa, Chordata	Ghrelin receptor of Homo sapiens (Q92847)
9.A.14.1.7	Photoreceptor melanopsin implicated in non-image formation in response to light.	Eukaryota	Metazoa, Chordata	Melanopsin of Xenopus laevis
9.A.14.1.8	Photoreceptor melanopsin that regulates circadian rhythms (Melyan et al. 2005).	Eukaryota	Metazoa, Chordata	Melanopsin of Homo sapiens
9.A.14.1.9	Rhadbomeric opsin of the clam worm.	Eukaryota	Metazoa, Annelida	Rhabdomeric opsin of Platynereesis dumerilii
9.A.14.1.10	Opsin of the green sea urchin	Eukaryota	Metazoa, Echinodermata	Opsin of Strongylocentrotus droebachiensis
9.A.14.1.11	G-protein coupled receptor 161, Gpr161 of 529 aas. Key negative regulator of Shh signaling and the sonic hedgehog pathway via cAMP signaling. Shh signalling promotes the processing of GLI3 into GLI3R during neural tube development (Mukhopadhyay et al. 2013).	Eukaryota	Metazoa, Chordata	Gpr161 of Homo sapiens
9.A.14.1.12	Rhodopsin of 359 aas and 7 TMSs, Rho or Zfo2. Light activated retinal release has been studied (Morrow and Chang 2015).	Eukaryota	Metazoa, Chordata	Zfo2 of Danio rerio (Zebrafish) (Brachydanio rerio)
9.A.14.1.13	Neurotensin receptor (β group of peptide-activated G-protein receptors) of 426 aas and 7 TMSs. Receptor for the neuromedin-U and neuromedin-S neuropeptides (Raddatz et al. 2000; Krumm and Grisshammer 2015).	Eukaryota	Metazoa, Chordata	Nmur1 of Homo sapiens
9.A.14.1.14	Neurotensin receptor type 1, Ntr1, of 418 aas and 7 TMSs. G-protein coupled receptor for the tridecapeptide neurotensin (NTS). Signaling is effected via G proteins that activate a phosphatidylinositol-calcium second messenger system. Signaling leads to the activation of downstream MAP kinases and protects cells against apoptosis (Da Costa et al. 2013).	Eukaryota	Metazoa, Chordata	Ntr1 of Homo sapiens
9.A.14.1.15	Zinc receptor, GPR39 of 453 aas and 7 TMSs. It localizes mainly to the sperm tail. Zn²⁺ at micromolar concentrations stimulates sperm hyperactivated motility, which is mediated by a cascade involving GPR39-adenylyl cyclase (AC)-cyclic AMP (cAMP)-protein kinase A-tyrosine kinase Src (Src)-epidermal growth factor receptor and phospholipase (Allouche-Fitoussi et al. 2018).	Eukaryota	Metazoa, Chordata	GPR39 of Homo sapiens
9.A.14.1.16	G-protein coupled receptor, GRL101-like protein of 340 aas and 7 TMSs.	Eukaryota	Metazoa, Placozoa	GPCR of Trichoplax sp. H2
9.A.14.1.17	Bovine rhodopsin of 348 aas and 7 TMSs. It is the photoreceptor required for image-forming vision at low light intensity. Also required for photoreceptor cell viability after birth. Light-induced isomerization of 11-cis to all-trans retinal triggers a conformational change that activates signaling via G-proteins (Singhal et al. 2016; Deupi et al. 2012). The x-ray structure has been determined at high resolution, and the folding and oligomerization (Okada and Palczewski 2001; Brown and Ernst 2017). This protein is 93% identical to the human ortholog (TC# 9.A.14.1.2).	Eukaryota	Metazoa, Chordata	Rhodopsin of Bos tauris
9.A.14.1.18	RH1 rhodopsin of 310 aas and 7 TMSs. This deep sea species dwells at depths of 1 - 2 km and has 38 rhodopsins, all similar in sequence, but different so that each one absorbs only an overlapping limited range of wavelengths (Musilova et al. 2019). This way they can detect biologically produced light in an ecosystem where no light from the sun penetrates (Pennisi 2019).	Eukaryota	Metazoa, Chordata	Rhodopsin of Diretmus argenteus (Silver spinyfin)
9.A.14.1.19	Relaxin receptor 1, RXFP1, of 757 aas and 7 C-terminal TMSs. It is a receptor for relaxins. The activity of this receptor is mediated by G proteins leading to stimulation of adenylate cyclase and an increase of cAMP. Binding of the ligand may also activate a tyrosine kinase pathway that inhibits the activity of a phosphodiesterase that degrades cAMP. H3 relaxin-mediates anti-inflammatory protection (Liu et al. 2020).	Eukaryota	Metazoa, Chordata	RXFP1 of Homo sapiens
9.A.14.1.20	Neurotensin receptor-2, NTR2 or NTR3, of 410 aas and 7 TMSs. Sortilin/NTSR3 (membrane-bound and soluble (extracellular) forms) are involved in many pathophysiological processes from cancer development to cardiovascular diseases, Alzheimer's disease, diabetes, and major depression (Mazella 2022).	Eukaryota	Metazoa, Chordata	NTR2 of Homo sapiens
9.A.14.1.21	Thirotropin receptor, isoform 1 precursor, of 764 aas with 7 TMSs in the C-terminal half of the protein. Also called the TSH receptor (TSHR). It is the receptor for the thyroid-stimulating hormone (TSH) or thyrotropin (Costagliola et al. 2002). It also acts as a receptor for the heterodimeric glycoprotein hormone (GPHA2:GPHB5) or thyrostimulin (Nakabayashi et al. 2002). The activity of this receptor is mediated by G proteins which activate adenylate cyclase (Costagliola et al. 2002). There are functional water channels within the TSH receptor that are activated 2-fold by TSH binding (Latif et al. 2023). TSHR-mediated disease risk can be modified by variants at the TSHR locus both inside and outside the coding region, and by altered TSHR-signaling and dietary iodine, supporting the need for personalized treatment strategies (Makkonen et al. 2024).	Eukaryota	Metazoa, Chordata	TSHR of Homo sapiens
9.A.14.2.1	Sphingosine 1-phosphate receptor, Edg1, Edg-1, CHEDG1 or S1PR1. The 3-d structure in known (Hanson et al., 2012). The activation mechanism has been proposed (Caliman et al. 2017). It plays an important role in cell migration, probably via its role in the reorganization of the actin cytoskeleton and the formation of lamellipodia in response to stimuli that increase the activity of the sphingosine kinase, SPHK1. It is also required for normal chemotaxis toward sphingosine 1-phosphate. Finally it is involved in responses to oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine by pulmonary endothelial cells (Singleton et al. 2009; Hanson et al. 2012). It is a biomarker for endometriosis (EM), a common gynecological disorder that often leads to irregular menstruation and infertility (Jiang et al. 2022).	Eukaryota	Metazoa, Chordata	Edg-1 of Homo sapiens (P21453)
9.A.14.2.2	Cannabinoid receptor 1, CB1 or CB-R, of 472 aas and 7 TMSs. The endocannabinoid system is widely present in the retina where it can modulate neurotransmitter release and ion channel activity (Bouchard et al. 2016). Endogenous endocannabinoids such as anandamide and 2-arachidonoyl glycerol (2AG) bind to the receptor and influence many processes including feeding, learning, memory, pain, emotions, sleep and dreams (Murillo-Rodriguez et al. 2017). Membrane lipids are integral parts of transmembrane allosteric sites in GPCRs as has been established with the cannabinoid CB1 receptor bound to a negative allosteric modulator, ORG27569, and analogs (Obi and Natesan 2022). All-atom molecular dynamics simulations have indicated the involvement of a conserved polar signaling channel in the activation mechanism of the type I cannabinoid receptor (Sarkar et al. 2023). In earlier studies of the mu-opioid and beta(2)-adrenergic receptors (MOP and beta(2)AR, respectively) these authors found that the orthosteric binding pockets and the intracellular surfaces of these receptors are connected through a channel of highly conserved polar amino acids whose dynamic motions are in high correlation in the agonist- and G protein-bound active states. This suggested that, in addition to consecutive conformational transitions, a shift of macroscopic polarization takes place in the transmembrane domain, which is furnished by the rearrangement of polar species through their concerted movements. Sarkar et al. 2023 examined the CB1 receptor signaling complexes utilizing microsecond scale, all-atom molecular dynamics (MD) simulations in order to see if the previous assumptions could be applied to the CB1 receptor. In addition to the identification of the previously proposed general features of the activation mechanism, several specific properties of CB1 were indicated that could be associated with the signaling profile of this receptor (Sarkar et al. 2023).	Eukaryota	Metazoa, Chordata	Cannabinoid receptor 1 of Homo sapiens (P21554)
9.A.14.2.3	Melanocortin receptor 4, MC4R, of 332 aas and 7 TMSs. At least 4% of childhood obesity is due to mutations in the hypothalamic MC4R which is important in the regulation of feeding behavior and body weight. MC4R activates the Galphaq/phospholipase C signaling pathway, resulting in alterations of cytoplasmic calcium in immortalized hypothalamic (GT1-1)neurons. Thus, upon agonist binding, MC4R mediates increases in intracellular calcium through the Galphaq-protein/phospholipase C dependent signaling pathway (Newman et al. 2006). MC4R binds to two neuropeptides, α-melanocyte-stimulating hormone [αMSH] and agouti-related protein [AgRP] which exert opposing effects on downstream responses. The 3-D structure of MC4R complexed with the cyclic peptide antogonist, SHU9119, revealed a Ca²⁺-binding site that influences downstream signaling (Chaturvedi and Shukla 2020). Israeli et al. 2021 presented the cryo-EM structure of the human MC4R-G_s signaling complex bound to the agonist setmelanotide, a cyclic peptide recently approved for the treatment of obesity. The work reveals the mechanism of MC4R activation, highlighting a molecular switch that initiates satiation signaling. Calcium (Ca²⁺) is required for agonist, but not antagonist, efficacy (Israeli et al. 2021). MC4R and TMEM18 (TC# 9.B.228) transcript abundances in sperm were positively correlated with the spermatozoa oxidative status (Correia et al. 2022).	Eukaryota	Metazoa, Chordata	MC4R of Homo sapiens (P32245)
9.A.14.2.4	ACTH-specific receptor, MC2R, in the melanocortin receptor family that includes MC1R - MC5R which recognize different melanocortin peptides. Domains responsible for specific membrane transport and lignad specificity in MC2R have been identified (Fridmanis et al. 2010). MC accessory protein (MRAP) facilitates MC2 receptor trafficking and allows properly localized receptor to bind ACTH and consequently signal (Sebag and Hinkle 2009).	Eukaryota	Metazoa, Chordata	MC2R of Homo sapiens
9.A.14.2.5	Lysophosphosphatidic acid (LPA) receptor, Edg4, of 351 aas and 7 TMSs. Mediates fibroblast chemotaxis (Ren et al. 2014), and forms a coplex with CFTR (3.A.1.202.1) (Zhang et al. 2017).	Eukaryota	Metazoa, Chordata	Edg4 of Homo sapiens
9.A.14.2.6	Cannabinoid receptor 2, CNR2. The endocannabinoid system is widely present in the retina where it can modulate neurotransmitter release and ion channel activity (Bouchard et al. 2016). Endogenous endocannabinoids such as anandamide and 2-arachidonoyl glycerol (2AG) bind to the receptor and influence many processes including feeding, learning, memory, pain, emotions, sleep and dreams (Murillo-Rodriguez et al. 2017). It plays a vital role in regulation of immune response, inflammation, pain, and other metabolic processes. Its 3-d structure has been studied by NMR (Yeliseev and Gawrisch 2017). EPR studies revealed that higher mobility was observed in the center of internal loop 3, and a structural change occurs between agonist vs. inverse agonist-bound CB2 in the extracellular tip of transmembrane helix 6 (Yeliseev et al. 2021).	Eukaryota	Metazoa, Chordata	CNR2 of Homo sapiens
9.A.14.2.7	G-protein coupled receptor, GPR3 or ACCA, of 330 aas and 7 TMSs. It is an orphan receptor with constitutive G(s) signaling activity that activates cyclic AMP. It has a potential role in modulating a number of brain functions, including behavioral responses to stress, amyloid-beta peptide generation in neurons and neurite outgrowth. It maintains meiotic arrest in oocytes. It is the most cold-induced G-coupled receptor in both brown and beige thermogenic adipose tissues. It has high basal Gs-coupled activity in the absence of an exogenous ligand (Sveidahl Johansen et al. 2021). It mimicks the cold induction of Gpr3 triggered cAMP production, activates the thermogenic response and counteracts meetabolic disease. A disease-associated genetic variant of GPR3 in patient-derived adiposctes revealed that GPR3 acts as a regulator of human thermogenic adipose tissue (Sveidahl Johansen et al. 2021).	Eukaryota	Metazoa, Chordata	GPR3 of Homo sapiens
9.A.14.3.1	Tyramine/octopamine receptor. Inhibited by amitraz metabolites (Casida and Durkin 2013).	Eukaryota	Metazoa, Platyhelminthes	Tyramine/octopamine receptor of Schistosoma mansoni (G4VI72)
9.A.14.3.2	The muscarinic acetylcholine G-protein-coupled receptor (Jo et al., 2010). Endothelial-dependent muscarinic receptor signaling acts largely through TRPV4 sparklet-mediated stimulation of IK (1.A.1.16.2) and SK (1.A.1.16.1) channels to promote vasodilation. There are five muscarinic receptor subtypes (M1R to M5R), which, despite sharing a high degree of sequence identity in the transmembrane region, couple to different heterotrimeric G proteins to transmit signals. M1R, M3R, and M5R couple to the G_q/ ₁₁ family, whereas M2R and M4R couple to the G_i/ _o family. Maeda et al. 2019 presented and compared the cryo-electron microscopy structures of M1R in complex with G₁₁ and M2R in complex with G_oA. The M1R-G₁₁ complex exhibits distinct features, including an extended transmembrane helix 5 and carboxyl-terminal receptor tail that interacts with the G protein. Detailed analysis provides a framework for understanding the molecular determinants of G-protein coupling selectivity (Maeda et al. 2019). The affinity of the seven-transmembrane muscarinic acetylcholine receptors for their agonists is modulated by membrane depolarization. Possibly this characteristic. Experiments measuring acetylcholine binding to muscarinic receptors in brain synaptoneurosomes suggest that gating of the voltage-dependent sodium channel (VDSC) acts as the voltage sensor, generating activation of Go-proteins in response to membrane depolarization, and this modulates the affinity of muscarinic receptors for their cholinergic agonists (Cohen-Armon 2023).	Eukaryota	Metazoa, Chordata	The muscarinic acetylcholine receptor (7TMSs; rhodopsin superfamily) of Mus musculus (P12657)
9.A.14.3.3	Tryamine receptor isoform A	Eukaryota	Metazoa, Arthropoda	Tyramine receptor of Drosophila melanogaster (E1JI27)
9.A.14.3.4	Adenosine receptor A1 of 326 aas and 7 TMSs. The ADORA1 mutation linked to early-onset Parkinson's disease alters adenosine A(1)-A(2A) receptor heteromer formation and function. Possibly, a hyperglutamatergic state secondary to increased constitutive activity and sensitivity to adenosine of A(2A)R not forming heteromers with A(1)R represent a main pathogenetic mechanism of the early onset Parkenson's Disease (EOPD) associated with the G279(7.44)S ADORA1 mutation (Sarasola et al. 2022).	Eukaryota	Metazoa, Chordata	Adenosine receptor A1 of Homo sapiens (P30542)
9.A.14.3.5	β-2 adrenergic receptor, β2-AR. Activates adenylate cyclase through G proteins. Binds epinephrine with 30x greater affinity than norepenephrine. Functions as an ATP-independent phospholipid flippase (scramblase) (Goren et al. 2014). A parameterized MARTINI program can be used to predict the hinging motions of the protein (Li et al. 2019). The drugs, salmeterol, formoterol and salbutamol, constitute the frontline treatment for asthma and other chronic pulmonary diseases. These drugs activate beta2-AR, and differ significantly in their clinical onset and durations of actions. Membrane lipids facilitate access and binding of the ligands, affecting their molecular recognition and pharmacology (Szlenk et al. 2021). Fullerene and fullerene derivatives affect the local structure of beta2AR, especially the distortion of helix4, but bring about no great changes within the overall structure (Li et al. 2019). The drugs, salmeterol, formoterol and salbutamol, constitute the frontline treatment for asthma and other chronic pulmonary diseases. These drugs activate beta2-AR, and differ significantly in their clinical onset and durations of actions. Membrane lipids facilitate access and binding of the ligands, affecting their molecular recognition and pharmacology (Szlenk et al. 2021). Fullerene and fullerene derivatives affect the local structure of beta2AR, especially the distortion of helix4, but bring about no great changes within the overall structure (Ren et al. 2022).	Eukaryota	Metazoa, Chordata	β-2-AR of Homo sapiens (P07550)
9.A.14.3.6	The serotonin or 5-hydroxytrytamine (5-HT) G protein-coupled receptor, 5HT1B. Wang et al (2013) reported the crystal structures of the human 5-HT1B bound to the agonist antimigraine medications ergotamine and dihydroergotamine. The structures revealed similar binding modes for these ligands, which occupy the orthosteric pocket and an extended binding pocket close to the extracellular loops. The orthosteric pocket is formed by residues conserved in the 5-HT receptor family.	Eukaryota	Metazoa, Chordata	5-HT1B of Homo sapiens
9.A.14.3.7	The serotonic or 5-hydroxytrytamine (5-HT) G protein-coupled receptor, 5HT2B. The structure of this receptor bound to ergotamine, the precursor of the hallucinogen, lysergic acid diethylamide, has been determined (Wacker et al., 2013). It reveals differences from those observed for 5-HT1B (9.B.14.3.6).	Eukaryota	Metazoa, Chordata	5-HT2B of Homo sapiens
9.A.14.3.8	Adenosine A2a receptor of 412 aas and 7 TMSs. It is a lipid flippase and a water channel (see below). The activity of this receptor is mediated by G proteins which activate adenylyl cyclase. The crystal structure has been solved revealing a continuous water channel (Yuan et al. 2015). Tryptophan-246 in TMS6 forms the gate. Conformational changes in TMSs 6 and 7 produce local changes in the lipid bilayer (Yuan et al. 2015). The protein can function as an ATP-independent phopholipid flippase (scramblase) (Goren et al. 2014). Yuan et al. 2015 found that the conserved W246(6.48) residue in transmembrane helix TM6 performs a key rotamer toggle switch. Agonist binding induces the sidechain of W246(6.48) to fluctuate between two distinct conformations, enabling the diffusion of water molecules from the bulk into the center of the receptor. After passing the W246(6.48) gate, the internal water molecules induce another conserved residue, Y288(7.53), to switch to a distinct rotamer conformation establishing a continuous transmembrane water pathway. Further, structural changes of TM6 and TM7 induce local structural changes of the adjacent lipid bilayer (Yuan et al. 2015). The human A2A adenosine receptor was structurally determined by microcrystal electron diffraction (MicroED) after converting the lipidic cubic phase (LCP) into the sponge phase followed by focused ion-beam milling. Martynowycz et al. 2021 determined the structure of the A2A adenosine receptor to 2.8 Å resolution and resolved an antagonist in its orthosteric ligand-binding site, as well as four cholesterol molecules bound around the receptor. Fusion protein strategies for cryo-EM study of this and other G protein-coupled receptors have been described (Zhang et al. 2022).	Eukaryota	Metazoa, Chordata	Adenosine receptor A2a of Homo sapiens
9.A.14.3.9	The dopamine receptor D3, DRD3 or D3R of 400 aas. Residues involved in receptor signaling have been identified (Kota et al. 2015), and several agonists are known (Xu et al. 2016). The atomic-level dopamine activation mechanism for transmitting extracellular ligand binding events through transmembrane helices to the cytoplasmic G protein has been elucidated (Weng et al. 2017). In agonist-bound systems, the D3R N-terminus forms a "lid-like" structure and lies flat on the binding site opening, whereas in antagonist-bound systems, the N-terminus exposes the binding cavity. A continuous water pathway is present only in the dopamine-Galphai-bound system. In the inactive D3Rs, water entry is hindered by the hydrophobic layers. It was proposed that upon agonist binding, the "lid-like" conformation of the N-terminus induces a series of molecular switches to increase the volume of the D3R cytoplasmic binding part for G protein association. Water enters the transmembrane region, inducing molecular switches to assist in opening the hydrophobic layers to form a continuous water channel, which is crucial for maintaining a fully active conformation for signal transduction (Weng et al. 2017). S-Deoxyephedrine can move through molecular channels within D3R (Li et al. 2017).	Eukaryota	Metazoa, Chordata	DRD3 of Homo sapiens
9.A.14.3.10	Dopamine receptor D2, DRD2, of 443 aas. Residues involved in signaling have been identified (Kota et al. 2015).	Eukaryota	Metazoa, Chordata	DRD2 of Homo sapiens
9.A.14.3.11	β1-adrenergic receptor of 477 aas and 7 TMSs. It can serve as an ATP-independent phospholipid flippase (scramblase) (Goren et al. 2014; Chauhan et al. 2016). Active-state structures of the β₁-adrenoceptor (β₁AR) bound to conformation-specific nanobodies in the presence of agonists of varying efficacy have been solved (Warne et al. 2019). Comparison with inactive-state structures of β₁AR bound to the identical ligands showed a 24 to 42% reduction in the volume of the orthosteric binding site. Potential hydrogen bonds were also shorter, and there was up to a 30% increase in the number of atomic contacts between the receptor and ligand. This explains the increase in agonist affinity of GPCRs in the active state for a wide range of structurally distinct agonists (Warne et al. 2019).	Eukaryota	Metazoa, Chordata	β1-adrenergic receptor of Homo sapiens
9.A.14.3.12	Serotonin receptor, Cg5-HTR-1, of 382 aas. It mediates immune responses in the oyster (Jia et al. 2018).	Eukaryota	Metazoa, Mollusca	Cg5-HTR-1 of Crassostrea gigas
9.A.14.3.13	The B96Bom octopamine receptor of 479 aas and 7 TMSs in a 5 + 2 TMS arrangement. The N-terminus of B96Bom, is N-myristoylated and translocated across the membrane (Utsumi et al. 2005).	Eukaryota	Metazoa, Arthropoda	B96Bom receptor of Bombyx mori
9.A.14.3.14	5-hydroxytryptamine receptor 1A, 5HTR1a, of 422 aas and 7 TMSs. G-protein coupled receptor for 5-hydroxytryptamine (serotonin) also functions as a receptor for various drugs and psychoactive substances (Harrington et al. 1994). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase (Gadgaard and Jensen 2020).	Eukaryota	Metazoa, Chordata	5HTR1a of Homo sapiens
9.A.14.3.15	5-hydroxytryptamine receptor-like protein of 540 aas and 7 TMSs in a 1 + 4 + 2 TMS arrangement.	Eukaryota	Metazoa, Mollusca	Receptor of Biomphalaria glabrata
9.A.14.3.16	The α2A adrenergic receptor in Family A GPCR; of 465 aas and 7 TMSs (Hilger et al. 2020).	Eukaryota	Metazoa, Chordata	Alpha2 AR of Homo sapiens
9.A.14.3.17	G-protein coupled receptor for 5-hydroxytryptamine (serotonin), 5-HTR2A of 471 aas and 7 TMSs (Cussac et al. 2008, Knauer et al. 2009). It also functions as a receptor for various drugs and psychoactive substances, including mescaline, psilocybin, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and lysergic acid diethylamide (LSD) (Wacker et al. 2017). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors. Beta-arrestin family members inhibit signaling via G proteins and mediate activation of alternative signaling pathways. Signaling activates phospholipase C and a phosphatidylinositol-calcium second messenger system that modulates the activity of phosphatidylinositol 3-kinase and promotes the release of Ca²⁺ ions from intracellular stores. It affects neural activity, perception, cognition and mood (González-Maeso et al. 2008), and plays a role in the regulation of behavior, while acting as a receptor for human JC polyomavirus/JCPyV (Assetta et al. 2013). Additionally, 5-HT stimulates PLC/IP3 receptor signals via the 5-HT2A receptor, and the tmAC/PKA/CatSper channel signals via the 5-HT4 receptor. After sAC and PKA are activated by these stimulations, sperm hyperactivation is enhanced (Sakamoto et al. 2021). Lee et al. 2023 identified an activation switch" motif common to all aminergic receptors. This motif includes the middle subsegments of TMSs 3, 5, and 6 and integrates both the PIF motif and Trp.	Eukaryota	Metazoa, Chordata	5-HT2A receptor of Homo sapiens
9.A.14.3.18	5-Hydroxytryptamine (serotonin) receptor 4, HTR4, of 338 aas and 7 TMSs. This is one of the several different receptors for 5-hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. The activity of this receptor is mediated by G proteins that stimulate adenylate cyclase. The tmAC/PKA/CatSper channel signals via the 5-HT4 receptor, and after sAC and PKA are activated by such stimulation, sperm hyperactivation is enhanced (Sakamoto et al. 2021).	Eukaryota	Metazoa, Chordata	HTR4 of Homo sapiens
9.A.14.3.19	C5a anaphylatoxin chemotactic receptor 1 of 463 aas and 7 TMSs in a 5 + 2 arrangement. The structural basis of sensory receptor evolution in the octopus has been revealed (Allard et al. 2023).	Eukaryota	Metazoa, Mollusca	C5a chemotaxis receptor of Octopus bimaculoides
9.A.14.3.20	Octopamine Receptor, OamB, of 645 aas and 7 TMSs. It is a receptor for octopamine (OA) which is a neurotransmitter, neurohormone and neuromodulator in invertebrates (Han et al. 1998). It stimulates intracellular accumulation of cAMP and Ca²⁺ following ligand binding (Balfanz et al. 2005). Leads to breakdown of the posterior follicle wall, resulting in ovulation (Deady and Sun 2015). Also plays a role in social behavior by modulating male agression (Luo et al. 2014).	Eukaryota	Metazoa, Arthropoda	OamB of Drosophila melanogaster
9.A.14.4.1	Calcitonin receptor	Eukaryota	Metazoa, Chordata	Calcitonin receptor of Homo sapiens (P30988)
9.A.14.4.2	PDF receptor	Eukaryota	Metazoa, Arthropoda	PDF receptor of Drosophila melanogaster (Q9W4Y2)
9.A.14.4.3	Corticotropin-releasing factor receptor-1, CRHR1. The structure is known (Hollenstein et al. 2013). Structural changes in CRFR1 upon antagonist binding and the role of single nucleotide polymorphisms have been investigated (Latek 2017). This G-protein coupled receptor for CRH (corticotropin-releasing factor) and UCN (urocortin) has high affinity for CRH and UCN. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and down-stream effectors such as adenylate cyclase. CRHR1 promotes the activation of adenylate cyclase, leading to increased intracellular cAMP levels. It inhibits the activity of the calcium channel CACNA1H (TC# 1.A.1.11.5) (Tao et al. 2008). Required for normal embryonic development of the adrenal gland and for normal hormonal responses to stress. Plays a role in the response to anxiogenic stimuli.	Eukaryota	Metazoa, Chordata	CRHR1 of Homo sapiens (P34998)
9.A.14.4.4	Diuretic hormone receptor	Eukaryota	Metazoa, Arthropoda	Diuretic hormone receptor of Acheta domesticus (Q16983)
9.A.14.4.5	Gastric inhibitory polypeptide receptor	Eukaryota	Metazoa, Chordata	Gastric inhibitory polypeptide receptor of Homo Sapiens (P48546)
9.A.14.4.6	Glucagon-like peptide 1 receptor, Glp-1, of 463 aas and 7 TMSs. It is a class B GPCR, a G-protein coupled receptor for glucagon-like peptide 1 (GLP-1) (Lau et al. 2015, Song et al. 2017). Ligand binding triggers activation of a signaling cascade that leads to the activation of adenylyl cyclase and increased intracellular cAMP levels (Hennen et al. 2016, Song et al. 2017). It plays a role in regulating insulin secretion in response to GLP-1. Water molecules contribute to activation of GLP-1R and resembles water dynamics in parts of the transmembrane region found in earlier studies of rhodopsin-like GPCRs (Poudel and Leitner, 2022). It increases preingestive satiation via hypothalamic circuits (Kim et al., 2024).	Eukaryota	Metazoa, Chordata	Glucagon-like peptide 1 receptor, Glp-1, of Homo sapiens (P43220)
9.A.14.4.7	Growth hormone-releasing hormone receptor	Eukaryota	Metazoa, Chordata	Growth hormone-releasing hormone receptor of Homo sapiens (Q02643)
9.A.14.4.8	Pituitary adenylate cyclase (AC)-activating polypeptide type 1 receptor of 468 aas and 7 TMSs. Aenylate cyclase 8E (AC8E) is a trunked form of adenylate cyclase in mammals that prevents the translocation of other ACs towards the plasma membrane, further reducing the cAMP responsiveness to extracellular signals. his dual inhibitory mechanism provides an additional level of regulation of cAMP-dependent signals integration (Legueux-Cajgfinger et al. 2023).	Eukaryota	Metazoa, Chordata	Pituitary adenylate cyclase-activating polypeptide type 1 receptor of Homo sapiens (P41586)
9.A.14.4.9	Vasoactive intestinal polypeptide receptor 1	Eukaryota	Metazoa, Chordata	Vasoactive intestinal polypeptide receptor 1 of Homo sapiens (P32241)
9.A.14.4.10	Secretin receptor	Eukaryota	Metazoa, Chordata	Secretin receptor of Homo sapiens (P47872)
9.A.14.4.11	Parathyroid hormone/parathyroid hormone-related peptide-1 receptor, PTH1R, of 573 aas and 8 or 9 TMSs in a 1 + 7 or 8 TMS arrangement. PTH1R is a class B G protein-coupled receptor central to calcium homeostasis and a therapeutic target for osteoporosis and hypoparathyroidism. Zhao et al. 2019 reported the cryo-EM structure of human PTH1R bound to a long-acting PTH analog and the stimulatory G protein. The bound peptide adopted an extended helix with its amino terminus inserted deeply into the receptor TMS, which led to partial unwinding of the carboxyl terminus of TMS6 and induceed a sharp kink at the middle of this helix to allow the receptor to couple with the G protein, while the extracellular domain adopted multiple conformations (Zhao et al. 2019). A cryoEM structure of a complex of G(s) and the human parathyroid hormone type 1 receptor (PTH1R) bound to a PTH1R agonist, PCO371 has been reported (Kobayashi et al. 2023). PCO371 binds within an intracellular pocket of PTH1R and directly interacts with G(s). The PCO371-binding mode rearranges the intracellular region towards the active conformation without extracellularly induced allosteric signal propagation (Kobayashi et al. 2023). PCO371 stabilizes the outward-bent conformation of TMS 6, which facilitates binding to G proteins rather than beta-arrestins. Furthermore, PCO371 binds within the conserved intracellular pocket, activating 7 out of the 15 class B1 GPCRs (Kobayashi et al. 2023). Thus, class B1 GPCR activation is mediated by an intracellular agonist.	Eukaryota	Metazoa, Chordata	Parathyroid hormone/parathyroid hormone-related peptide receptor of Homo sapiens (Q03431)
9.A.14.4.12	Calcitonin gene-related peptide type 1 receptor (CGRP type 1 receptor) (Calcitonin receptor-like receptor). It is involved in the regulation of vascular tone and the modulatioin of inflammatory and metabolic responses (Hendrikse et al. 2019). The high resoution 3-d structure is known, revealing its mechanism of receptor activation, including the conformational dynamics that occur upon agonist binding (Josephs et al. 2021).	Eukaryota	Metazoa, Chordata	CALCRL of Homo sapiens
9.A.14.4.13	Glucagon receptor of 477 aas and 7 TMSs (Family B GPCR; Hilger et al. 2020) (MacNeil et al. 1994). It is the G-protein coupled receptor for glucagon that plays a central role in the regulation of blood glucose levels and glucose homeostasis (Zhou et al. 2009). It does so by regulating the rate of hepatic glucose production by promoting glycogen hydrolysis and gluconeogenesis, and it mediates the responses to fasting. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Promotes activation of adenylate cyclase and plays a role in signaling via a phosphatidylinositol-calcium second messenger system. The 3-D structure has been determined (Siu et al. 2013; Zhang et al. 2017). In addition, its structure with glucagon and two distinct classes of heterotrimeric G-proteins, G_s and G_i1, has been determined (Qiao et al. 2020; Chang et al. 2020).	Eukaryota	Metazoa, Chordata	GCGR of Homo sapiens
9.A.14.5.1	Cyclic AMP receptor 1	Eukaryota	Evosea	Cyclic AMP receptor 1 of Dictyostelium discoideum (P13773)
9.A.14.5.2	GCR1 of 326 aas and 7 TMSs. Together with GPA1, may regulate the cell cycle via a signaling cascade that uses phosphatidylinositol-specific phospholipase C (PI-PLC) as an effector and inositol 1,4,5-trisphosphate (IP₃) as a second messenger. Mediates responses to blue light and abscisic acid (Warpeha et al. 2007).	Eukaryota	Viridiplantae, Streptophyta	GCR1 of Arabidopsis thaliana (Mouse-ear cress)
9.A.14.5.3	Putative cyclic AMP receptor of 428 aas and 7 TMSs (Kulkarni et al. 2005).	Eukaryota	Fungi, Ascomycota	cAMP receptor of the plant pathogenic fungus, Magnaporthe grisea (Rice blast fungus) (Pyricularia oryzae)
9.A.14.6.1	EGF-like module-containing mucin-like hormone receptor-like 1	Eukaryota	Metazoa, Chordata	EGF-like module-containing mucin-like hormone receptor-like 1 of Homo sapiens (Q14246)
9.A.14.6.2	CD97 antigen or adhesion GPCR (aGPCR, ADGRE5), of 835 aas amd 7 C-terminal TMSs, with one possible N-terminal TMS. The protein plays a role in tumorigenesis (Aust et al. 2016). Maser and Calvet 2020 reviewed structural and functional features shared by polycystin-1 (TC# 1.A.5.1.1) and the adhesion GPCRs and discussed the implications of such similarities for our understanding of the functions of this complicated protein (Thor and Liebscher 2023). The stachel binding site is within the 7TMS domain (Kleinau et al. 2023). The analyses of these authors extend the current view of aGPCR activation and exposes similarities and differences not only between diverse aGPCR members, but also compared to other GPCR classes.	Eukaryota	Metazoa, Chordata	CD97 antigen of Homo sapiens (P48960)
9.A.14.6.3	EGF, latrophilin and seven transmembrane domain-containing protein 1	Eukaryota	Metazoa, Chordata	EGF, latrophilin and seven transmembrane domain-containing protein 1 of Homo sapiens (Q9HBW9)
9.A.14.6.4	Cadherin EGF LAG seven-pass G-type receptor 1, CELSR1 of 3014 aas and 7 TMSs near the C-terminus. Association of CELSR1 with Frizzled-6 in Drosophiila melanogaster (see TC# 9.A.14.16.1 for Frizzeled-1) is important, enabling efficient Frizzled-6 delivery to the cell surface, providing a quality-control mechanism that ensures appropriate stoichiometry of these two planar cell polarity (PCP) proteins at cell boundaries (Tang et al. 2020).	Eukaryota	Metazoa, Chordata	Cadherin EGF LAG seven-pass G-type receptor 1 of Homo sapiens (Q9NYQ6)
9.A.14.6.5	Latrophilin receptor (Lat-2)	Eukaryota	Metazoa, Nematoda	Lat-2 of Caenorhabditis elegans (B2MZA8)
9.A.14.6.6	Brain-specific angiogenesis inhibitor 2	Eukaryota	Metazoa, Chordata	Brain-specific angiogenesis inhibitor 2 of Homo sapiens (O60241)
9.A.14.6.7	Adhesin G-protein-coupled receptor, BAI3 (ARGRB3) of 1522 aas. It plays a role in the regulation of synaptogenesis and dendritic spine formation, at least partly via interaction with ELMO1 and RAC1. It promotes myoblast fusion through ELMO/DOCK1 (Hamoud et al. 2014). Complement 1q-like protein inhibits insulin secretion froms pancreatic β-cells via BAI3 (Gupta et al. 2018).	Eukaryota	Metazoa, Chordata	BAI3 of Homo sapiens (Human)
9.A.14.6.8	Adhesion 6 protein-coupled receptor, ADGRL3, or latrophilin-3, LPHN3, of 1447 aas and 7 central TMSs. It plays a role in cell-cell adhesion and neuron guidance via its interactions with FLRT2 and FLRT3 that are expressed at the surface of adjacent cells (Lu et al. 2015). It also plays a role in the development of glutamatergic synapses in the cortex and determines the connectivity rates between the principal neurons in the cortex. Knockout of latrophilin-3 in rats causes hyperactivity, hyper-reactivity, under-response to amphetamine, and disrupted dopamine markers (Regan et al. 2019).	Eukaryota	Metazoa, Chordata	ADGRL3 of Homo sapiens
9.A.14.6.9	LATROPHILIN-2, ADGRL2 or Adhesion G protein-coupled receptor L2, LEC1, LPHH1, LPHN2 of 1459 aas. It is a calcium-independent receptor of low affinity for alpha-latrotoxin, an excitatory neurotoxin present in black widow spider venom which triggers massive exocytosis from neurons and neuroendocrine cells. This receptor has been implicated in the regulation of exocytosis (Moreno-Salinas et al. 2019; Burbach and Meijer 2019).	Eukaryota	Metazoa, Chordata	ADGRL2 of Homo sapiens
9.A.14.6.10	Adhesion G-protein coupled receptor G2, ADGRG2, of 1017 aas and 8 TMSs, one N-terminal and 7 C-terminal. It may be involved in a signal transduction pathway controlling epididymal function and male fertility as well as fluid exchange within the epididymis (Wu et al. 2020). β-arrestin-1 acts as a scaffold for ADGRG2/CFTR complex formation in apical membranes, whereas specific residues of ADGRG2 confer coupling specificity for different G protein subtypes, which is critical for male fertility (Zhang et al. 2018).	Eukaryota	Metazoa, Chordata	ADGRG2 of Homo sapiens
9.A.14.6.11	Full length G-protein coupled receptor 98 (GPR98) of 6306 aas and 7 C-terminal TMSs. It is also called the monogenic audiogenic seizure susceptibility protein 1 homologue, the usher syndrome type-2C protein, and the very large G-protein coupled receptor 1 (VLGR1). It plays a role in CNS development and exists as multiple processed isoforms.	Eukaryota	Metazoa, Chordata	GPR98 of Homo sapiens
9.A.14.6.12	Noelin1 (Olfactomedin-1) of 467 aas and one N-terminal TMS. It regulates and is an interactor of AMPAR ( see family description for TC# 1.A.10).	Eukaryota	Metazoa, Chordata	Noelin1 of Homo sapiens
9.A.14.7.1	Metabotropic glutamate receptor 1, class C. The parallel 7 TMS dimer is mediated by cholesterol, which suggests that signaling initiated by glutamate's interaction with the extracellular domain might be mediated via 7 TMS interactions within the full-length receptor dimer (Wu et al. 2014). This protein appears to be involved in regulation of the functions of glycine receptors (see TC# 1.A.9.3.1) (Zhang et al. 2019).	Eukaryota	Metazoa, Chordata	Metabotropic glutamate receptor 1 of Homo sapiens (Q13255)
9.A.14.7.2	Extracellular calcium-sensing receptor of 1078 aas and 7 TMSs, designated CASR, GPRC2A, and PCAR1. It senses changes in the extracellular concentration of calcium ions and plays a key role in maintaining calcium homeostasis (Kim et al. 2016). In the inner ear membranous labyrinth, CaSR localizes exclusively to mitochondrion-rich cells, suggesting a unique role of the endolymphatic sac epithelium in CaSR-mediated sensing and control (Bächinger et al. 2019). The basolateral Ca²⁺-sensing receptor (TC# 9.A.14.7.2) has the ability to downregulate the activity of the NKCC1 transporter upon activation. Once transported into the tubule cells, sodium ions are actively transported across the basolateral membrane by the Na⁺,K⁺-ATPases, and chloride ions pass by facilitated diffusion through basolateral chloride channels. Potassium, however, is able to diffuse back into the tubule lumen through apical potassium channels, returning a net positive charge to the lumen and establishing a positive voltage between the lumen and interstitial space. This charge gradient is obligatory for the paracellular reabsorption of both calcium and magnesium ions. The calcium-sensing receptor (CaSR) modulates ocular surface chloride transport, and its inhibition promotes ocular surface hydration (Pasricha et al. 2024).	Eukaryota	Metazoa, Chordata	Extracellular calcium-sensing receptor of Homo sapiens (P41180)
9.A.14.7.3	G-protein coupled receptor family C group 6 member A	Eukaryota	Metazoa, Chordata	G-protein coupled receptor family C group 6 member A of Homo sapiens (Q5T6X5)
9.A.14.7.4	Taste receptor type 1 member 2, TAS1R2, GPR71, TR2, of 839 aas and 7 C-terminal TMSs. Sweet substances are detected by taste-bud cells upon binding to the sweet-taste receptor, a T1R2/T1R3 heterodimeric G protein-coupled receptor (von Molitor et al. 2020).	Eukaryota	Metazoa, Chordata	Taste receptor type 1 member 2 of Homo sapiens (Q8TE23)
9.A.14.7.5	Taste receptor type 1 member 1, TAS1	Eukaryota	Metazoa, Chordata	TAS1 of Homo spaiens
9.A.14.7.6	Vomeronasal type-2 receptor 1, Vmn2r1, of 912 aas and 7 C-terminal TMSs.	Eukaryota	Metazoa, Chordata	Vmn2r1 of Mus musculus
9.A.14.7.7	G-protein coupled receptor family C group 6 member A, Gprc6a, of 877 aas and 7 C-terminal TMSs. It is an olfactory receptor that is activated by amino acids that act as potent odorants in fish. It is most highly activated by basic amino acids such as L-lysine and L-arginine (Speca et al. 1999).	Eukaryota	Metazoa, Chordata	Gprc6a of Carassius auratus (Goldfish)
9.A.14.7.8	Metabotropic glutamate receptor 5, mGluR5, GRM5, of 1212 aas and 7 TMSs. It is a G-protein-coupled receptor for glutamate. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors. Signaling activates a phosphatidylinositol-calcium second messenger system and generates a calcium-activated chloride current. GRM5 plays a role in the regulation of synaptic plasticity and the modulation of the neural network activity (Minakami et al. 1994). The structure of the transmembrane domain has been determined (Doré et al. 2014). The prevalence, presentation, and progression of Alzheimer's disease (AD) differ between men and women, although β-amyloid (Aβ) deposition is a pathological hallmark of AD in both sexes. Aβ-induced activation of the neuronal glutamate receptor mGluR5 is linked to AD progression. However, mGluR5 exhibits distinct sex-dependent profiles (Abd-Elrahman et al. 2020). mGluR5 isolated from male mouse cortical and hippocampal tissues bound with high affinity to Aβ oligomers, whereas mGluR5 from female mice exhibited no such affinity. This sex-selective Aβ-mGluR5 interaction is not depend on estrogen, but rather Aβ interaction with cellular prion protein (PrP^C), which was detected only in male mouse brain homogenates. The ternary complex between mGluR5, Aβ oligomers, and PrP^C was essential to elicit mGluR5-dependent pathological suppression of autophagy in primary neuronal cultures. Pharmacological inhibition of mGluR5 reactivated autophagy, mitigated Aβ pathology, and reversed cognitive decline in male APPswe/PS1ΔE9 mice, but not in their female counterparts. Aβ oligomers also bound with high affinity to human mGluR5 isolated from postmortem donor male cortical brain tissue, but not that from female samples, suggesting that this mechanism may be relevant to patients. mGluR5 does not contribute to Aβ pathology in females, highlighting the complexity of mGluR5 pharmacology and Aβ signaling that supports the need for sex-specific stratification in clinical trials assessing AD therapeutics (Abd-Elrahman et al. 2020). Co-activation of NMDAR and mGluRs controls protein nanoparticle-induced osmotic pressure in neurotoxic edema (Zheng et al. 2023).	Eukaryota	Metazoa, Chordata	GRM5 of Homo sapiens
9.A.14.7.9	Glutamate metabolomic receptor 2, Grm2, of 872 aas with 1 N-terminal and 7 C-terminal TMSs. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling inhibits adenylate cyclase activity (Flor et al. 1995). It may mediate suppression of neurotransmission or may be involved in synaptogenesis or synaptic stabilization. It forms a complex with the serotonin receptor (González-Maeso et al. 2008) as well as with SNAT6, the glutamate/glutamine transporter (Gandasi et al. 2021).	Eukaryota	Metazoa, Chordata	Grm2 of Homo sapiens
9.A.14.7.10	Taste receptor TAS1R3, T1R3, TR3 of 852 aas and 7 C-terminal TMSs. TAS1R1/TAS1R3 responds to the umami (amino acid) taste stimuli (the taste of monosodium glutamate) (Li et al. 2002). TAS1R2/TAS1R3 recognizes diverse natural and synthetic sweeteners (Li et al. 2002), and this heterodimer as well as TAS1R1/TAS1R3 confers sweet-sensing abilities to songbirds (nearly half of all birds) (Toda et al. 2021). TAS1R3 is essential for the recognition and response to the disaccharide trehalose (Ariyasu et al. 2018). Sequence differences within and between species can significantly influence the selectivity and specificity of taste responses. This receptor may function in a parallel sweet-sensitive pathway, involving signaling mechanisms, neural processing, interactions with endocrine hormonal mechanisms, and sensitivity to different stimuli, and its physiological role in detecting the energy content of food in preparation for digestion (von Molitor et al. 2020).	Eukaryota	Metazoa, Chordata	TAS1R3 of Homo sapiens
9.A.14.8.1	Olfactory receptor 1E1	Eukaryota	Metazoa, Chordata	Olfactory receptor 1E1 of Homo sapiens (P30953)
9.A.14.8.2	Olfactory receptor, OR2AG1 of 316 aas and 7 TMSs (Song et al. 2009).	Eukaryota	Metazoa, Chordata	Olfactory receptor, OR2AG1 of Homo sapiens
9.A.14.8.3	Olfactory receptor OR51E2 of 320 aas and 7 TMSs. This olfactory receptor (Jovancevic et al. 2017) is activated by the odorant, beta-ionone, a synthetic terpenoid (Neuhaus et al. 2009). Its activity is propably mediated by G-proteins leading to the elevation of intracellular Ca²⁺, cAMP and activation of the protein kinases PKA and MAPK3/MAPK1 (Gelis et al. 2016). Stimulation of OR51E2 by beta-ionone affects melanocyte proliferation, differentiation, and melanogenesis and increases proliferation and migration of primary retinal pigment epithelial cells (Jovancevic et al. 2017). Activation by the short-chain fatty acids (SCFA), acetate, L-lactate and propionate, may positively regulate renin secretion and increase blood pressure (Pluznick et al. 2013). It may also be activated by steroid hormones and regulate cell proliferation (Neuhaus et al. 2009). The orthologues from bovine species are ~ 92% identical to the human ortholog, and there appears to be an expansion in the gene copt number of olfactory receptors (Neuhaus et al. 2009). Its activity is propably mediated by G-proteins leading to the elevation of intracellular Ca²⁺, cAMP and activation of the protein kinases PKA and MAPK3/MAPK1 (Gelis et al. 2016). Stimulation of OR51E2 by beta-ionone affects melanocyte proliferation, differentiation, and melanogenesis and increases proliferation and migration of primary retinal pigment epithelial cells (Jovancevic et al. 2017). Activation by the short-chain fatty acids (SCFA), acetate, L-lactate and propionate, may positively regulate renin secretion and increase blood pressure (Pluznick et al. 2013). It may also be activated by steroid hormones and regulate cell proliferation (Neuhaus et al. 2009). The orthologues from bovine species are ~ 92% identical to the human ortholog, and there appears to be an expansion in the gene copt number of olfactory receptors (Low et al. 2022).	Eukaryota	Metazoa, Chordata	OR51E2 of Homo sapiens
9.A.14.9.1	Prostaglandin E2 receptor EP1 subtype	Eukaryota	Metazoa, Chordata	Prostaglandin E2 receptor EP1 subtype of Homo sapiens (P34995)
9.A.14.9.2	Prostaglandin E2 receptor, EP3 subtype, of 390 aas and 7 TMSs. Receptor for prostaglandin E2 (PGE2) (Adam et al. 1994). The activity of this receptor can couple to both the inhibition of adenylate cyclase mediated by G(i) proteins, and to an elevation of intracellular calcium (Kunapuli et al. 1994). It is required for normal development of fever in response to pyrinogens, including IL1B, prostaglandin E2 and bacterial lipopolysaccharide (LPS). It is required for normal potentiation of platelet aggregation by prostaglandin E2, and thus plays a role in the regulation of blood coagulation. Also required for increased HCO3^- secretion in the duodenum in response to mucosal acidification, and thereby contributes to the protection of the mucosa against acid-induced ulceration, but it is not required for normal kidney function, normal urine volume and osmolality. It is a biomarker for endometriosis (Adam et al. 1994; Jiang et al. 2022).	Eukaryota	Metazoa, Chordata	PTGER3 of Homo sapiens
9.A.14.10.1	Gonadotropin-releasing hormone receptor	Eukaryota	Metazoa, Chordata	Gonadotropin-releasing hormone receptor of Homo sapiens (P30968)
9.A.14.10.2	Renal vasopressin receptor V1b (Hagiwara et al. 2013).	Eukaryota	Metazoa, Chordata	Vasopressin receptor V1b of Homo sapiens
9.A.14.10.3	Vasopressin (receptor 2, AVPR2, AVP2, AVPV2) of 371 aas and 7 TMSs. Pharmacochaperones post-translationally enhance cell surface expression of V2 by increasing the conformational stability of wild-type and mutant vasopressin V2 receptors (Wüller et al. 2004). New developments and concepts in the diagnosis and management of diabetes insipidus (AVP-deficiency and resistance) have been summarized and involve AVPR2 (Angelousi et al. 2023).	Eukaryota	Metazoa, Chordata	AVPR2 of Homo sapiens
9.A.14.10.4	Dimeric oxytosin receptor, OxtR, of 389 aas and 7 TMSs. Superpotent behavior follows from the binding of oxytosin receptor-specific bivalent ligands to dimeric receptors based on a TMS1-TMS2 interface, and in this arrangement, only analogues with a well-defined spacer length (approximately 25 Å) precisely fit inside a channel-like passage between the two protomers of the dimer (Busnelli et al. 2016). The oxytocin receptor (OXTR) is involved in parturition and lactation of mammals as well as their emotional and social behaviors. Cholesterol acts on OXTR as an allosteric modulator, inducing a high-affinity state for orthosteric ligands. Stable binding of cholesterol to the receptor when it adopts an orthosteric ligand-bound state preserves the cholesterol-dependent activity of the receptor (Lemel et al. 2021).	Eukaryota	Metazoa, Chordata	OxtR of Homo sapiens
9.A.14.10.5	G-protein coupled receptor, NPSR1, for neuropeptide S (NPS) and promotes mobilization of intracellular Ca²⁺ stores (Bernier et al. 2006). It also inhibits cell growth in response to NPS binding (Vendelin et al. 2005). It is involved in the pathogenesis of asthma and other IgE-mediated diseases (Xu et al. 2004; Bernier et al. 2006).	Eukaryota	Metazoa, Chordata	NPSR1 of Homo sapiens
9.A.14.10.6	Arginine vasotocin receptor of 419 aas and 7 TMSs (Kang et al. 2019). The vasotocin receptor family is homologous to mammalian vasopressin G-protein coupled receptors (Jayanthi et al. 2014).It controls water flow via aquaporin-2 in the kidney (Yang et al. 2004).	Eukaryota	Metazoa, Chordata	Arginine vasotocin receptor of Gallus gallus
9.A.14.11.1	G-protein-coupled receptor, GH10049p	Eukaryota	Metazoa, Arthropoda	GH10049p of Drosophila melanogaster (Q8MSJ2)
9.A.14.11.2	G-protein-coupled receptor, GPCR, family C, group 5 member C, isoform a	Eukaryota	Metazoa, Chordata	GPCR of Homo sapiens (Q9NQ84)
9.A.14.11.3	GPRC5B of 403 aas and 8 TMSs in a 1 + 7 TMS arrangement. It is a players in controlling brain oedema (brain volume regulation) (Passchier et al. 2023). Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is the prototype. These findings shed light on the protein complex involved in astrocyte volume regulation and identify GPRC5B as novel potentially druggable target for treating brain oedema (asschier et al. 2023).	Eukaryota	Metazoa, Chordata	GPRC4B of Homo sapiens
9.A.14.12.1	Vomeronasal type-1 receptor 1 of 353 aas and 7 TMSs.	Eukaryota	Metazoa, Chordata	Vomeronasal type-1 receptor 1 of Homo sapiens (Q9GZP7)
9.A.14.12.2	Vomeronasal 1 receptor of 300 aas and 7 TMSs.	Eukaryota	Metazoa, Chordata	Vomeronasal 1 receptor of Oryctolagus cuniculus
9.A.14.12.3	Vomeronasal type-1 receptor 3-like of 321 aas and 7 TMSs.	Eukaryota	Metazoa, Chordata	Vomeronasal receptor of Cyprinodon variegatus
9.A.14.12.4	Vomeronasal type-1 receptor of 341 aas and 7 TMSs.	Eukaryota	Metazoa, Chordata	Vomeronasal receptor of Equus asinus
9.A.14.13.1	Type-1a angiotensin II receptor of 395 aas and 7 or 8 TMSs, AGTR1(A and B), AT2R1, AT2R1B. A single mutation in the amphipahtic helix 8 enhances its transport and signalling (Zhu et al. 2015). It is a biomarker for endometriosis (EM), a common gynecological disorder that often leads to irregular menstruation and infertility (Jiang et al. 2022). Angiotensin II and Losartan-induced gene regulatory networks have been revealed using human urine-derived podocytes (Thimm et al. 2023).	Eukaryota	Metazoa, Chordata	Type-1 angiotensin II receptor of Homo sapiens (P30556)
9.A.14.13.2	Cysteinyl leukotriene receptor 1	Eukaryota	Metazoa, Chordata	Cysteinyl leukotriene receptor 1 of Homo sapiens (Q9Y271)
9.A.14.13.3	Platelet-activating factor receptor	Eukaryota	Metazoa, Chordata	Platelet-activating factor receptor of Homo sapiens (P25105)
9.A.14.13.4	G-protein coupled receptor 81, GPR81 or Hydroxycarboxylic acid receptor 1 (HCAR1), of 346 aas and 7 TMSs. It acts as a receptor for L-lactate and mediates its anti-lipolytic effect through a G(i)-protein-mediated pathway (Liu et al. 2009). Lactate inhibits lipolysis in fat cells through activation of the orphan G-protein-coupled receptor, GPR81. Lactate is generally associated with hypoxia, inflammation, viral infections, and tumors. It performs complex physiological roles by activating monocarboxylate transporter (MCT) or the G protein-coupled receptor GPR81 across the cell membrane. Lactate exerts immunosuppressive effects by regulating the functions of various immune cells (such as natural killer cells, T cells, dendritic cells, and monocytes) (Liu et al. 2024).	Eukaryota	Metazoa, Chordata	G-protein coupled receptor 81 of Homo sapiens (Q9BXC0)
9.A.14.13.5	Leukotriene B4 receptor 1	Eukaryota	Metazoa, Chordata	Leukotriene B4 receptor 1 of Homo sapiens (Q15722)
9.A.14.13.6	Melanin-concentrating hormone receptor 1	Eukaryota	Metazoa, Chordata	MCHR1 of Homo sapiens
9.A.14.13.7	Mas-related G-protein coupled receptor member F (Mas-related gene F protein) (G-protein coupled receptor 140) (G-protein coupled receptor 168)	Eukaryota	Metazoa, Chordata	MRGPRF of Homo sapiens
9.A.14.13.8	G-protein-coupled receptor GPR35. Agonists include the tryptophan metabolite kynurenic acid, the synthetic ligand zaprinast and two thiazolidinediones. Agonist activation involves TMSIII and is transduced via Galpha(1)(3) and beta-arrestin-2 (Jenkins et al. 2011). Specific GPR35 agonists should be developed for the treatment of ischemic diseases (Wyant et al. 2022). GPR35-expressing hematopoietic cells respond to the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA). Sources of serotonin and 5-HIAA are platelets and mast cells. Multiple platelet and mast cell-derived mediators, including 5-HIAA, cooperate to promote neutrophil recruitment (De Giovanni et al. 2023).	Eukaryota	Metazoa, Chordata	GPR35 of Homo sapiens
9.A.14.13.9	Lysophosphatidic acid receptor 4 (LPA-4; G-protein receptor 23; purinoreceptor 9 (purinurgic receptor 9), P2Y9. The C-terminal tail directs the protein to the apical membrane of polarized epithelial cells (DuBose et al. 2013).	Eukaryota	Metazoa, Chordata	LPA-4 of Homo sapiens
9.A.14.13.10	The apelin hormone receptor (angiotensin receptor; GPCR APJ; GPCR HC11) of 380 aas. The human apelin (77 aas) receptor is coupled to G proteins that inhibit adenylate cyclase activity. It plays a role in various processes in adults such as regulation of blood pressure, heart contractility, and heart failure. During heart formation, it acts as a receptor for elabela hormone (ELA). It influences cell movement during embryonic development and serves as an alternative coreceptor with CD4 for HIV-1 infection (Pauli et al. 2014); it may also be involved in the development of AIDS dementia. Elevated Na⁺ is a dynamic and reversible modulator of mitochondrial metabolism in the heart (Chung et al. 2024).	Eukaryota	Metazoa, Chordata	Apelin receptor of Homo sapiens
9.A.14.13.11	Uncharacterized protein of 317 aas and 7 TMSs. Shows sequence similarity to proteins in 9.B.190.	Eukaryota	Metazoa, Chordata	UP of Danio rerio (Zebrafish) (Brachydanio rerio)
9.A.14.13.12	Proteinase-activated receptor-2 of 397 aas and 7 TMSs (δ group), F2RL1, GPR11, PAR2, or PAR-2. Receptor for trypsin and trypsin-like enzymes coupled to G proteins. Its function is mediated through the activation of several signaling pathways including phospholipase C (PLC), intracellular calcium, mitogen-activated protein kinase (MAPK), I-kappaB kinase/NF-kappaB and Rho. It can also be transactivated by cleaved F2R/PAR1. It is involved in modulation of inflammatory responses and regulation of innate and adaptive immunity, and it acts as a sensor for proteolytic enzymes generated during infection (Krumm and Grisshammer 2015). PAR-2, the second member of the G protein-coupled PAR family, is irreversibly activated by trypsin or tryptase and then targeted to lysosomes for degradation. Intracellular presynthesized receptors stored at the Golgi apparatus repopulate the cell surface after trypsin stimulation, thereby leading to rapid resensitization to trypsin signaling (Luo et al. 2007). p24A, a type I transmembrane protein, controls ARF1-dependent resensitization of PAR-2 by influencing receptor trafficking (Luo et al. 2007).	Eukaryota	Metazoa, Chordata	PAR2 of Homo sapiens
9.A.14.13.13	Neuropeptides B/W receptor type 2, Npbwr2 of 333 aas and 7 TMSs. Of the γ-group. Interacts specifically with a number of opioid ligands. Receptor for neuropeptides B and W, which may be involved in neuroendocrine system regulation, food intake and the organization of other signals (Krumm and Grisshammer 2015).	Eukaryota	Metazoa, Chordata	Npbwr2 of Homo sapiens
9.A.14.13.14	The KiSS receptor (KiSSR) or G-protein receptor 54. Receptor for metastin (kisspeptin-54 or kp-54), a C-terminally amidated peptide of KiSS1. KiSS1 is a metastasis suppressor protein that suppresses metastases in malignant melanomas and in some breast carcinomas without affecting tumorigenicity. Kisspeptin and GABA interact to modulate secretion and reproduction (Di Giorgio et al. 2019).	Eukaryota	Metazoa, Chordata	KiSS receptor of Homo sapiens
9.A.14.13.15	Chemokine-like receptor 1, Cmklr1, of 373 aas and 7 TMSs. Receptor for the chemoattractant, adipokine chemerin/RARRES2, and for the omega-3 fatty acid-derived molecule, resolvin E1. Interaction with RARRES2 induces activation of intracellular signaling molecules leading to multifunctional effects, e.g., reduction of immune responses, enhancment of adipogenesis and angionesis. Resolvin E1 down-regulates cytokine production in macrophages. Positively regulates adipogenesis and adipocyte metabolism (Krumm and Grisshammer 2015). Genetic and epigenetic insights into the chemokines and their receptors have been reviewed (Xu et al. 2023). Aquaporin-8 ameliorates hepatic steatosis through the farnesoid X receptor in obese mice (Xiang et al. 2023).	Eukaryota	Metazoa, Chordata
9.A.14.13.16	The P2Y purinoreceptor 2, P2Y2 of 377 aas and 7 TMSs. Receptor for ATP and UTP coupled to G-proteins that activate a phosphatidylinositol-calcium second messenger system. The affinity range is UTP = ATP > ATP-gamma-S >> 2-methylthio-ATP = ADP. Plays a role in shedding (Pupovac and Sluyter 2016). There are eight mammalian P2Y receptor subtypes (P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13, and P2Y14), and they play a variety of roles in cell physiology (von Kügelgen and Hoffmann 2016). The 3-d x-ray structure of a P2Y2 receptor is known (Jacobson et al. 2015). Antagonists stabilize an ionic lock within the P2T1 receptor, but binding of ADP breaks this ionic lock, forming a continuous water channel that leads to P2Y1 receptor activation (Yuan et al. 2016).		Metazoa, Chordata	P2Y2 of Homo sapiens
9.A.14.13.17	Chemokine receptor type 4, CXCR4 of 352 aas and 7 TMSs. The majority of essential residues form a continuous intramolecular signaling chain through the transmembrane helices. This chain connects chemokine binding residues on the extracellular side of CXCR4 to G protein-coupling residues on its intracellular side. Integrated into a cohesive model of signal transmission, these CXCR4 residues cluster into five functional groups that mediate (i) chemokine engagement, (ii) signal initiation, (iii) signal propagation, (iv) microswitch activation, and (v) G protein coupling. Propagation of the signal passes through a "hydrophobic bridge" on helix VI (Wescott et al. 2016).	Eukaryota	Metazoa, Chordata	CXCR4 of Homo sapiens
9.A.14.13.18	Mu-type opioid receptor, OPRM1 (OprM1) or MOR of 400 aas and 7 TMSs. Receptor for endogenous opioids such as beta-endorphin and endomorphin and for natural and synthetic opioids including morphine, heroin, DAMGO, fentanyl, etorphine, buprenorphin and methadone. Agonist binding to the receptor induces coupling to an inactive GDP-bound heterotrimeric G-protein complex and subsequent exchange of GDP for GTP in the G-protein alpha subunit leading to dissociation of the G-protein complex with the free GTP-bound G-protein alpha and the G-protein beta-gamma dimer activating downstream cellular effectors. The agonist- and cell type-specific activity is predominantly coupled to pertussis toxin-sensitive G(i) and G(o) G alpha proteins, GNAI1, GNAI2, GNAI3 and GNAO1 isoforms Alpha-1 and Alpha-2, and to a lesser extend to pertussis toxin-insensitive G alpha proteins GNAZ and GNA15. They mediate an array of downstream cellular responses, including inhibition of adenylate cyclase activity as well as both N-type and L-type calcium channels, and activation of inward rectifying potassium channels (Knapman and Connor 2015). Activation of the astrocytic μ-opioid receptor elicits fast glutamate release through TREK-1-containing K2P channel in hippocampal astrocytes (Woo et al. 2018).	Eukaryota	Metazoa, Chordata	OprM1 of Homo sapiens
9.A.14.13.19	The G-protein-coupled estrogen receptor, GPER (Gpr30; GPER1) of 375 aas and 7 TMSs. GPER binds to 17-beta-estradiol (E2) with high affinity and aldosterone with lower affinity, leading to rapid and transient activation of numerous intracellular signaling pathways. Activating GPR30 by estrogen results in intracellular calcium mobilization and synthesis of phosphatidylinositol 3,4,5-trisphosphate in the nucleus. Thus, GPR30 represents an intracellular transmembrane estrogen receptor that may contribute to normal estrogen physiology as well as pathophysiology. It stimulates cAMP production, calcium mobilization and tyrosine kinase Src (Gros et al. 2013; Gaudet et al. 2015).	Eukaryota	Metazoa, Chordata	GPER of Homo sapiens
9.A.14.13.20	Prosaposin receptor, Gpr37 of 613 aas and 7 TMSs. Receptor for the neuroprotective and glioprotective factor, prosaposin. Ligand binding induces endocytosis, followed by an ERK phosphorylation cascade (Meyer et al. 2013).	Eukaryota	Metazoa, Chordata	Prosaposin receptor of Homo sapiens
9.A.14.13.21	Prorelaxin receptor RXFP3 (RLN3R1, SALPR) of 469 aas and 7 TMSs. Relaxin is an ovarian hormone that acts with estrogen to produce dilatation of the birth canal in many mammals. Cholesterol modulates the binding properties of human RXFP3 with its ligands, enhancing that of some, and decreasing that of others (Wang et al. 2018).	Eukaryota	Metazoa, Chordata	RXFP3 of Homo sapiens
9.A.14.13.22	P2Y1 purinoceptor of 373 aas and 7 TMSs. Receptor for extracellular adenine nucleotides such as ATP and ADP. In platelets binding to ADP leads to mobilization of intracellular calcium ions via activation of phospholipase C, a change in platelet shape, and probably to platelet aggregation (Jin et al. 1998).	Eukaryota	Metazoa, Chordata	P2Y1 of Homo sapiens
9.A.14.13.23	Receptor for somatostatin-14 and -28 of 418 aas and 7 TMSs, SSTR3. This receptor is coupled via pertussis toxin sensitive G proteins to inhibition of adenylyl cyclase (Yamada et al. 1992). Motility and signaling functions of the primary cilium require a unique protein and lipid composition that is determined by gating mechanisms localized at the base of the cilium, and SSTR3 plays a direct role (Takao et al. 2017). B9D1, AHI1, and the N termini of NPHP4 and NPHP5 interact with SSTR3 and thus spatially map to the outer region of the ciliary gating zone.	Eukaryota	Metazoa, Chordata	SSTR3 of Homo sapiens
9.A.14.13.24	Long neuropeptide F receptor (NPFR) isoform 1 of 390 aas and 7 TMSs. NPFR may play roles within the CNS in digestion and possibly egg production and/or egg development in R. prolixus (Sedra et al. 2018).	Eukaryota	Metazoa, Arthropoda	NPFR of Rhodnius prolixus
9.A.14.13.25	G-protein coupled receptor 139, GPR139, GPRG1 or PGR3, of 353 aas and 7 TMSs. It is an orphan receptor that seems to act through a G(q/11)-mediated pathway. GPR139 and the dopamine D2 receptor co-express in the same cells of the brain and may functionally interact (Wang et al. 2019). Loss of GPR139 enhanced effects of morphine in mice but reduced withdrawal effects (Wang et al. 2019). It is a regulator of opioid receptors (Lindsay and Scherrer 2019).	Eukaryota	Metazoa, Chordata	GPR139 of Homo sapiens
9.A.14.13.26	C5a anaphylatoxin chemotactic receptor 1 of 350 aas and 7 TMSs. Receptor for the chemotactic and inflammatory peptide anaphylatoxin C5a (Robertson et al. 2018).	Eukaryota	Metazoa, Chordata	C5a anaphylatoxin receptor of Homo sapiens
9.A.14.13.27	Receptor for bradykinin of 392 aas and 7 TMSs. It is associated with G proteins that activate a phosphatidylinositol-calcium second messenger system (Tang et al. 2018).	Eukaryota	Metazoa, Chordata	Bradykinin receptor of Homo sapiens
9.A.14.13.28	Putative biopolymer transport system, comprising a probable proton channel, ExbB/ExbD (Slr0677/Slr0678). These proteins energize one or more outer membrane receptors (1.B.14); probably involved in iron-siderophore uptake. ExbD interacts directly with TonB (TC# 2.C.1.3.1) (Qiu et al. 2018).	Eukaryota	Metazoa, Chordata	ExbB/ExbD of Synechocystis sp. (strain PCC 6803 / Kazusa)
9.A.14.13.29	Free fatty acid receptor-4, FFAR4, or GPR120, of 361 aas and 7 TMSs. GPR120 is a long-chain fatty acid receptor that stimulates incretin hormone release from colonic endocrine cells and is implicated in macrophage and adipocyte function (Watson et al. 2012). Cryo-EM structures have revealed how fatty acid hormones bind the orthosteric site within the 7 TMS domain within GPCRs (Mao et al. 2023). FFAR4 is a regulator of food and water intake (Apuschkin et al. 2024).	Eukaryota	Metazoa, Chordata	FFAR4 of Homo sapiens
9.A.14.13.30	Free fatty acid receptor-1, FFAR1 or GPR40, of 300 aas and 7 TMSs. G-protein coupled receptor for medium and long chain saturated and unsaturated fatty acids that plays an important role in glucose homeostasis (Briscoe et al. 2003). Fatty acid binding increases glucose-stimulated insulin secretion, and may also enhance the secretion of glucagon-like peptide 1 (GLP-1) (Suckow et al. 2014). May also play a role in bone homeostasis; receptor signaling activates pathways that inhibit osteoclast differentiation (Philippe et al. 2016). Ligand binding leads to a conformation change that triggers signaling via G-proteins that activate phospholipase C, leading to an increase of the intracellular calcium concentration (Li et al. 2020). The receptor is strongly activated by gamma-linolenic acid, while myristate gives a lower response. It is also activated by phytanic acid and pristanic acid (Kruska and Reiser 2011).	Eukaryota	Metazoa, Chordata	FFAR1 of Homo sapiens
9.A.14.13.31	Platelet P2Y purinoceptor 12, P2Y12 or P2YR12, of 342 aas and 7 TMSs. It is a receptor for ADP and ATP coupled to G-proteins that inhibit the adenylyl cyclase second messenger system. It is not activated by UDP and UTP. It is required for normal platelet aggregation and blood coagulation (Hollopeter et al. 2001). Clopidogrel is a potent antithrombotic drug that targets the P2Y12 receptor and inhibits ADP-induced platelet aggregation (Herbert and Savi 2003). The structure has been determined (Zhang et al. 2014) with and without agonist (Zhang et al. 2014). KDKE is a conserved functional motif for sugar binding in both P2Y14 and P2Y purinoceptor 12 (P2Y12), and three sugar nucleotides as agonists of P2Y12 have been identified (Zhao et al. 2023).	Eukaryota	Metazoa, Chordata	P2Y12 of Homo sapiens (Human)
9.A.14.13.32	Kappa-opioid receptor, KOR, of 380 aas and 7 TMSs. Sperm-specific protein changes occur downstream of KOR in human spermatozoa (Urizar-Arenaza et al. 2019). It functions as a receptor for endogenous alpha-neoendorphins and dynorphins, but has low affinity for beta-endorphins. It also functions as a receptor for the psychoactive diterpene salvinorin A. Ligand binding causes a conformation change that triggers signaling via G proteins and modulates the activity of down-stream effectors, such as adenylate cyclase (Wu et al. 2012). Co-targeting the kappa opioid receptor and dopamine transporter reduces motivation to self-administer cocaine and partially reverses dopamine system dysregulation (Estave et al. 2024).	Eukaryota	Metazoa, Chordata	Kappa opioid receptor, KOR, of Homo sapiens
9.A.14.13.33	Neuropeptide Y receptor type 2, NPYR2, of 381 aas and 7 TMSs. It is a receptor for neuropeptide Y and peptide YY. The rank order of affinity of this receptor for pancreatic polypeptides is PYY > NPY > PYY (3-36) > NPY (2-36) > [Ile-31, Gln-34] PP > [Leu-31, Pro-34] NPY > PP, [Pro-34] PYY and NPY free acid. Neuropeptide Y (NPY) and NPY receptors are widely expressed in the central nervous system, including the retina. Retinal cells express this peptide and its receptors (Y1, Y2, Y4 and/or Y5), and NPY is expressed in the retina of various mammalian and non-mammalian species. Its early expression strongly suggests that NPY may be involved in the development of retinal circuitry. NPY inhibits the increase in [Ca²⁺]_i, triggered by elevated KCl in retinal neurons, due to inhibition of Ca²⁺ channels, and it protects retinal neural cells against toxic insults while inducing the proliferation of retinal progenitor cells. Santos-Carvalho et al. 2014 reviewed the roles of NPY in the retina, specifically proliferation, neuromodulation and neuroprotection. Alterations in the NPY system in the retina might contribute to the pathogenesis of retinal degenerative diseases, such as diabetic retinopathy and glaucoma.	Eukaryota	Metazoa, Chordata	YPN2 of Homo sapiens
9.A.14.13.34	The Duffy antigen, DARC or ACKR1, FY, GPD, of 336 aas and 7 TMSs. It is an atypical chemokine receptor that controls chemokine levels and localization via high-affinity chemokine binding that is uncoupled from classic ligand-driven signal transduction cascades, resulting instead in chemokine sequestration, degradation, or transcytosis. It is also known as interceptor (internalizing receptor) or chemokine-scavenging receptor or chemokine decoy receptor. Almost the entire populations of DARC and three other transmembrane proteins are immobilized by either the incorporation within large multiprotein complexes or entrapment within the protein network of the cortical spectrin cytoskeleton (Kodippili et al. 2020).	Eukaryota	Metazoa, Chordata	DARC of Homo sapiens
9.A.14.13.35	Atypical chemokine receptor, C5aR2, that controls chemokine levels and localization via high-affinity chemokine binding that is uncoupled from classic ligand-driven signal transduction cascades, resulting instead in chemokine sequestration, degradation, or transcytosis. It is also known as interceptor (internalizing receptor) or chemokine-scavenging receptor or chemokine decoy receptor. Acts as a receptor for chemokines including CCL2, CCL3, CCL3L1, CCL4, CCL5, CCL7, CCL8, CCL11, CCL13, CCL17, CCL22, CCL23, CCL24, SCYA2/MCP-1, SCY3/MIP-1-alpha, SCYA5/RANTES and SCYA7/MCP-3. Upon active ligand stimulation, it activates a beta-arrestin 1 (ARRB1)-dependent, G protein-independent signaling pathway that results in the phosphorylation of the actin-binding protein cofilin (CFL1) through a RAC1-PAK1-LIMK1 signaling pathway. Activation of this pathway results in up-regulation of ACKR2 from endosomal compartment to cell membrane, increasing its efficiency in chemokine uptake and degradation (McKimmie et al. 2013; Borroni et al. 2013).	Eukaryota	Metazoa, Chordata	D6R of Homo sapiens
9.A.14.13.36	Somatostatin receptor type 1, SSTR1, of 391 aas and 7 TMSs. Prostate-specific membrane antigen, Lutetium-177, is a transmembrane protein found predominately on the prostate epithelium and is expressed at high levels in prostate cancer. It's properties have been reviewed (Jia et al. 2022).	Eukaryota	Metazoa, Chordata	SSTR1 of Homo sapiens
9.A.14.13.37	Protease-activated receptor_1 of 425 aas and 7 TMSs, PAR1, F2R, CF2R. It activates the KCNN3 channel. Dextran sodium sulfate (DSS) treatment causes loss of transient relaxations due to downregulation of SK3 channels (TC#1.A.1.16.7) and may increase contractile responses due to increased Ca²⁺ sensitization of smooth muscle cells via PAR1 activation (Sung et al. 2022). ().	Eukaryota	Metazoa, Chordata	PAR1 of Homo sapiens
9.A.14.13.38	Prokineticin receptor 1 (ProKR1) of 393 aas and 7 TMSs. Receptor for prokineticin 1. It is exclusively coupled to the G(q) subclass of heteromeric G proteins. Activation leads to mobilization of calcium, stimulation of phosphoinositide turnover and activation of p44/p42 mitogen-activated protein kinase. It may play a role during early pregnancy (Evans et al. 2008). It is 87% identical to ProKR2, a receptor that binds the ligand prokineticin 2, involved in pleasant touch (Liu et al. 2022).	Eukaryota	Metazoa, Chordata	ProKR1 of Homo sapiens
9.A.14.13.39	N-arachidonyl glycine receptor, GPR18, of 331 aas and 7 TMSs. It is a receptor for endocannabinoid N-arachidonyl glycine (NAGly) (Flegel et al. 2016). It can also be activated by plant-derived and synthetic cannabinoid agonists (Console-Bram et al. 2014). The activity of this receptor is mediated by G proteins which inhibit adenylyl cyclase (Kohno et al. 2006). It may contribute to the regulation of the immune system.	Eukaryota	Metazoa, Chordata	GPR18 of Homo sapiens
9.A.14.13.40	G-protein-coupled receptor 183, GPR183, of 361 aas and 7 TMSs. This G-protein-coupled receptor is expressed in lymphocytes. It acts as a chemotactic receptor for B-cells, T-cells, splenic dendritic cells, monocytes/macrophages and astrocytes. It is a receptor for oxysterol 7-alpha,25-dihydroxycholesterol (7-alpha,25-OHC) and other related oxysterols (Hannedouche et al. 2011, Zhang et al. 2012). It mediates cell positioning and movement of a number of cells by binding the 7-alpha,25-OHC ligand that forms a chemotactic gradient. Binding of 7-alpha,25-OHC mediates the correct localization of B-cells during humoral immune responses. GPR183 is a chemotactic receptor with a function in the immune system, association with a variety of diseases. It recognizes ligands with diverse physicochemical properties, as both the endogenous oxysterol ligand 7α,25-OHC and synthetic molecules can activate the G protein pathway of the receptor. Ligand entry pathways control the chemical space recognized by GPR183 (Kjær et al. 2023).	Eukaryota	Metazoa, Chordata	GPR183 of Homo sapiens
9.A.14.13.41	Type 2 angiotensin II receptor, AGTR2, of 363 aas and 7 TMSs.	Eukaryota	Metazoa, Chordata	AGTR2 of Homo sapiens
9.A.14.13.42	G-protein receptor 20, Gpr20, of 358 aas and 7 TMSs. It is an orphan receptor with constitutive G(i) signaling activity that activate cyclic AMP (Hase et al. 2008). Its ortholog may play a role in milk production in cows (Persichilli et al. 2023).	Eukaryota	Metazoa, Chordata	GPR20 of Homo sapiens
9.A.14.13.43	Hydroxycarboxylic acid receptor 3, HCAR3, of 387 aas and 7 TMSs. It is a receptor for 3-OH-octanoid acid and mediates a negative feedback regulation of adipocyte lipolysis to counteract prolipolytic influences under conditions of physiological or pathological increases in beta-oxidation rates. It acts as a low affinity receptor for nicotinic acid, but this pharmacological effect requires nicotinic acid doses that are much higher than those provided by a normal diet (Wise et al. 2003; Ahmed et al. 2009). GPR109A interacts with hippuric acid (Bhandari et al. 2022).	Eukaryota	Metazoa, Chordata	HCAR3 of Homo sapiens
9.A.14.13.44	n-Formyl peptide receptor-2, FRP2, of 351 aas and 7 TMSs, is a G-protein receptor. It is a Low affinity receptor for N-formyl-methionyl peptides, which are powerful neutrophil chemotactic factors (Ye et al. 1992). Binding of FMLP to the receptor causes activation of neutrophils. This response is mediated via a G-protein that activates a phosphatidylinositol-calcium second messenger system (Ye et al. 1992). The activation of LXA4R could result in an anti-inflammatory outcome counteracting the actions of pro-inflammatory signals such as LTB4 (leukotriene B4) (Gronert et al. 1998). It is also a receptor for the chemokine-like protein FAM19A5, mediating FAM19A5-stimulated macrophage chemotaxis and the inhibitory effect on TNFSF11/RANKL-induced osteoclast differentiation. It also acts as a receptor for humanin (Harada et al. 2004). FPR2 agonist AnxA1 treatment resulted in the upregulation of the FPR2/p-ERK(1/2)/DUSP1/CD36 signaling pathway (Flores et al. 2023).	Eukaryota	Metazoa, Chordata	FRP2 of Homo sapiens
9.A.14.13.45	GPR4 of 362 aas and 7 TMSs. It is a proton-sensing G-protein coupled receptor that couples to multiple intracellular signaling pathways (Chen et al. 2011). It could potentially be used as therapeutic targets and diagnostic biomarkers for the development of novel broad spectrum therapeutic agents (Jia et al. 2023).	Eukaryota	Metazoa, Chordata	GPR4 of Homo sapiens
9.A.14.13.46	P2Y purinoceptor 14, P2RY14, of 338 aas and 7 TMSs, a drug target for inflammation and immune responses. The mode of activation of purinergic receptors and insight into the carbohydrate drug development for GPCRs have been examined (Zhao et al. 2023).	Eukaryota	Metazoa, Chordata	P2RY14 of Homo sapiens
9.A.14.13.47	Free fatty acid receptor 2, FFAR2, of 330 aas and 7 TMSs. It is a G protein-coupled receptor that is activated by a major product of dietary fiber digestion, the short chain fatty acids (SCFAs), and that plays a role in the regulation of whole-body energy homeostasis and in intestinal immunity.	Eukaryota	Metazoa, Chordata	FFAR2 of Homo sapiens
9.A.14.13.48	Free fatty acid receptor 3 (FFAR3) of 346 aas and 7 TMSs. This protein is similar to FFAR2 in sequence and function (see 9.A.14.131.47). The short chain fatty acids acetate, propionate and butyrate are produced primarily by the gut microbiome that metabolizes dietary fibers. SCFAs serve as a source of energy but also act as signaling molecules.	Eukaryota	Metazoa, Chordata	FFAR3 of Homo sapiens
9.A.14.14.1	Probable G-protein coupled receptor Mth-like 10	Eukaryota	Metazoa, Arthropoda	Probable G-protein coupled receptor Mth-like 10 of Drosophila melanogaster (Q9W0R5)
9.A.14.14.2	Methuselah (Mth) G-protein receptor. Involved in biological aging and stress responses. Essential for adult survival. Required in the presynaptic motor neuron to up-regulate neurotransmitter exocytosis at larval glutamatergic neuromuscular junctions. Regulates a step associated with docking and clustering of vesicles at release sites.	Eukaryota	Metazoa, Arthropoda	Methusalah of Drosophila melanogaster
9.A.14.15.1	Gamma-aminobutyric acid type B receptor subunit 2	Eukaryota	Metazoa, Chordata	Gamma-aminobutyric acid type B receptor subunit 2 of Homo sapiens (O75899)
9.A.14.15.2	Probable G-protein coupled receptor CG31760	Eukaryota	Metazoa, Arthropoda	CG31760 of Drosophila melanogaster
9.A.14.15.3	Metabolomic GABA-B receptor, GrlE or GluPR, of 816 aas and 7 TMSs. May be involved in the early development of cAMP sensing and subsequent chemotactic responses. It is the receptor for GABA and glutamate, leading respectively to the induction or inhibition of SDF-2 formation (Anjard and Loomis 2006; Prabhu et al. 2007).	Eukaryota	Evosea	GrlE of Dictyostelium discoideum (Slime mold)
9.A.14.15.4	Metabolomic GABAB receptor (GABABR, GPR156, GABABL, PGR28) of 814 aas and 7 N-terminal TMSs in a 4 + 3 TMS arrangement. It plays a role in idiopathic pulmonary fibrosis (IPF), a rare persistent lung disorder that actuates scarring of lung tissues, making breathing difficult (Mishra et al. 2021).	Eukaryota	Metazoa, Chordata	GABAB receptor of Homo sapiens
9.A.14.15.5	Metabotropic glycine receptor, GPR158 (mGlyR), of 1215 aas and 8 or 9 TMSs in a 1 (N-terminal) + 7 (residues 420 - 660). possibly with one more at about residue 345. It acts by altering the concentration of cAMP. Glycine is recognized by aCachedomain in GlyR to regulate the activities of cartical neurons (Laboute et al. 2023).	Eukaryota	Metazoa, Chordata	GPR158 of Homo sapiens
9.A.14.15.6	Probable G-protein coupled receptor 179, GPR179, of 2367 aas and 7 TMSs, possibly with one additional TMS at the N-terminus of the protein. The Cryo-EM structure of human class C orphan GPCR GPR179 is involved in visual processing (Yun et al. 2024). GPR179, an orphan class C GPCR, is expressed at the dendritic tips of ON-bipolar cells in the retina. It plays a pivotal role in the initial synaptic transmission of visual signals from photoreceptors, and its deficiency is known to be the cause of complete congenital stationary night blindness. The transmembrane domain (TMD) of GPR179 forms a homodimer through the TM1/7 interface with a single inter-protomer disulfide bond, adopting a noncanonical dimerization mode. The TMD dimer exhibits architecture well-suited for the highly curved membrane of the dendritic tip and distinct from the flat membrane arrangement observed in other class C GPCR dimers. This structure reveals unique structural features of GPR179 TMD, setting it apart from other class C GPCRs. These findings provide a foundation for understanding signal transduction through GPR179 in visual processing and offers insights into the underlying causes of ocular diseases (Yun et al. 2024).	Eukaryota	Viridiplantae, Streptophyta	GPR179 of Homo sapiens
9.A.14.16.1	Frizzled-1, FZD1 of 647 aas and 8 to 11 TMSs with 1 - 4 TMSs near the N-terminus, and 7 TMSs near the C-terminus. Receptor for Wnt proteins. Most of frizzled receptors are coupled to the beta-catenin canonical signaling pathway, which leads to the activation of disheveled proteins, inhibition of GSK-3 kinase, nuclear accumulation of beta-catenin and activation of Wnt target genes. A second signaling pathway involving PKC and calcium fluxes has been seen for some family members. Association of Frizzled-6 from Drosophila melanogaster with CELSR1 (see TC# 9.A.14.6.4) is important, enabling efficient Frizzled-6 delivery to the cell surface, providing a quality-control mechanism that ensures appropriate stoichiometry of these two planar cell polarity (PCP) proteins at cell boundaries (Tang et al. 2020).	Eukaryota	Metazoa, Chordata	FZD1 of Homo sapiens
9.A.14.16.2	Frizzled-2, Fe2 of 694 aas and 7 TMSs. Receptor for Wnt proteins. Most frizzled receptors are coupled to the beta-catenin canonical signaling pathway, which leads to the activation of disheveled proteins, inhibition of GSK-3 kinase, nuclear accumulation of beta-catenin and activation of Wnt target genes. A second signaling pathway involving PKC and calcium fluxes has been seen for some family members, but it is not yet clear if it represents a distinct pathway or can be integrated in the canonical pathway, as PKC seems to be required for Wnt-mediated inactivation of GSK-3 kinase. Both pathways seem to involve interactions with G-proteins. Required to coordinate the cytoskeletons of epidermal cells to produce a parallel array of cuticular hairs and bristles (Hsieh et al. 1999).	Eukaryota	Metazoa, Arthropoda	Fr2 of Drosophila melanogaster (Fruit fly)
9.A.14.16.3	Frizzled 6, FZD6 of 712 aas and 7 TMSs. FZD6 functions in multiple signal transduction pathways, for example, as a receptor in Wnt/planar cell polarity (PCP) signaling pathway for polarized cell migration and organ morphogenesis. Mutations in FZD6 have been identified in a variety of tumors (Zou et al. 2017). Sfz6 mRNA is ubiquitously expressed, being highest in kidney and heart, and moderate in jejunum, ileum, colon, liver, and spleen.In the jejunum, FZD6 protein is more prevalent in the villus than in the crypt cells (Zou et al. 2017). FZD6 forms dimers, whose association is regulated by WNT proteins, and dimer dissociation is crucial for FZD6 signaling (Petersen et al. 2017).	Eukaryota	Metazoa, Chordata	FZD6 of Sus scrofa (Pig)
9.A.14.16.4	G-protein homologue, Smoothed; Smo; Smoh, of 787 aas and 7 TMSs (Lum and Beachy 2004). It is regulated via the Hedgehog pathway by the RND-like protein, Patched1 ((PTCH1; TC# 2.A.6.6.13) (Myers et al. 2017). The cryoEM structure of SMO bound to Patched reveals that SMO has a channel open to the membrane as well as to the extracellular cysteine-rich domain (CRD). This domain, like that in Patched, is large enough to accomodate cholesterol, so SMO could be a transporter as well as a receptor (Sommer and Lemmon 2018; Qi et al. 2018). Sterols in an intramolecular channel of Smoothened mediate Hedgehog signaling (Qi et al. 2020). SMO, a class Frizzled G protein-coupled receptor (class F GPCR), transduces the Hedgehog signal across the cell membrane. Sterols can bind to its extracellular cysteine-rich domain (CRD) and to several sites in the seven transmembrane helices (7 TMSs) of SMO. Qi et al. 2020 determined the structures of SMO-Gi complexes bound to the synthetic SMO agonist (SAG) and to 24(S),25-epoxycholesterol (24(S),25-EC). A novel sterol-binding site in the extracellular extension of TMS6 was revealed to connect other sites in the 7-TMSs and CRD, forming an intramolecular sterol channel from the middle side of 7-TMSs to CRD. Additional structures of two gain-of-function variants, SMO(D384R) and SMO(G111C/I496C), showed that blocking the channel at its midpoints allows sterols to occupy the binding sites in 7-TMSs, thereby activating SMO. Thus, sterol transport through the core of SMO is a major regulator of SMO-mediated signaling. These observations show that like other 7 TMS GPCRs, SMO is capable of transport, in this case, transporting cholesterol (Qi et al. 2020). The regulatory activities of cellular lipids and sterols has been measured during Hedgehog signaling (Deshpande and Manglik 2022). The activation mechanism of class F GPCRs has been elucidated, and it shows that SMO's activation process rearranges the core TMSs to open a hydrophobic conduit for cholesterol transport (Bansal et al. 2023).	Eukaryota	Metazoa, Chordata	Smoothed of Homo sapiens
9.A.14.16.5	Frizzled, Fz, of 468 aas and 7 TMSs, a receptor for Wnt proteins. Involved in transcriptional regulation of synapse development (Mathew et al. 2005). It is a target of insecticides (Audsley and Down 2015). Its targeting from the ER to the plasma membrane has been studied (Tang et al., 2020; PMID# 33516494). ).	Eukaryota	Metazoa, Arthropoda	Frizzled of Drosophila melanogaster (Fruit fly)
9.A.14.16.6	Protein smoothened, Smo, of 1036 aas and 7 TMSs, fairly centrally located. Glycolysis regulates Hedgehog (Hh) signalling via the plasma membrane potential, and Smo regulates this signalling (Spannl et al. 2020). The regulatory activities of cellular lipids and sterols has been measured during Hedgehog signaling (Deshpande and Manglik 2022).	Eukaryota	Metazoa, Arthropoda	Smo of Drosophila melanogaster (Fruit fly)
9.A.14.16.7	Secreted frizzled-related protein 1, SFRP1, FRP-1, sFRP-1, secreted apoptosis-related protein 2, SARP-2 of 314 aas and 1 TMS. It is a potential target of oral squamous cell carcinoma (OSCC) (Chen et al. 2022). Highly expressed SFRP1 is associated with membrane potential and passive transmembrane transporter activity and is mainly enriched in calcium pathway and neuroactive ligand-receptor interaction (Chen et al. 2022). Thus, SFRP1 expression provides insight into the risk and prognostic stratification in OSCC.	Eukaryota	Metazoa, Chordata	SFRP1 of Homo sapiens
9.A.14.17.1	Taste receptor type 2 member 1, TAS2. Glutamate (bitter) taste receptor expressed in the tongue and palate epithelia.	Eukaryota	Metazoa, Chordata	TAS2 of Homo sapiens
9.A.14.17.2	Taste receptor type 2 member 4 of 299 aas and 7 TMSs, TAS2R4.	Eukaryota	Metazoa, Chordata	TAS2R4 of Homo sapiens
9.A.14.17.3	Taste receptor type 2 member 40 of 315 aas and 7 TMSs, TAS2R40.	Eukaryota	Metazoa, Chordata	TAS2RX of Latimeria chalumnae (West Indian ocean coelacanth)
9.A.14.17.4	Taste receptor type 2 of 316 aas and 7 TMSs, TR2	Eukaryota	Metazoa, Chordata	TR2 of Pelodiscus sinensis (Chinese softshell turtle) (Trionyx sinensis)
9.A.14.17.5	Taste receptor type 2 member 38 (T2R38; bitter taste receptor of 333 aas and 7 TMSs) (Gaida et al. 2016). Activated by the bona fide ligand for T2R38, phenylthiourea (PTU), and by N-acetyl-dodecanoyl homoserine (AHL-12), a quorum sensing molecule of Pseudomonas aeruginosa. The latter is the only known natural ligand for T2R38. In response to PTU or AHL-12, key transcription factors are activated including phosphorylation of the MAP kinases p38 and ERK1/2, and upregulation of NFATc1. Increased expression of the multi-drug resistance protein 1 (ABCB1, TC# 3.A.1.201.1) is also observed, a transporter that shuttles a plethora of drugs, such as chemotherapeutics and antibiotics (Gaida et al. 2016).	Eukaryota	Metazoa, Chordata	Bitter taste receptor of Homo sapiens
9.A.14.17.6	Bitter taste receptor, TAS2R46, of 309 aas and 7 TMSs. This receptor may play a role in the perception of bitterness and is gustducin-linked. It may sense the chemical composition of the gastrointestinal content. The activity of this receptor may stimulate alpha gustducin, mediate PLC-beta-2 activation and lead to the gating of TRPM5. In airway epithelial cells, binding of bitter compounds increases the intracellular calcium ion concentration and stimulates ciliary beat frequency. Most taste cells are activated by a limited number of bitter compounds, and individual taste cells can discriminate among bitter stimuli. The structural basis for strychnine activation of TAS2R46 has been determined (Xu et al. 2022).	Eukaryota	Metazoa, Chordata	TAS2R46 of Homo sapiens
9.A.14.18.1	Cytomegalovirus M78 receptor of 473 aas and 7 TMSs. It's trafficing has been studied (Sharp et al. 2009). This protein is a member of the β-herpesvirus 'UL78 family' of seven transmembrane receptors which are required for efficient cell-cell spread of the virus in tissue culture, and M78 knockout viruses are attenuated for replication in vivo. M78 forms dimers, a property common to several cellular 7TMR. It traffics to the cell surface but is rapidly and constitutively endocytosed. In MCMV-infected cells, the subcellular localization of M78 is modified during the course of infection, which may be related to the incorporation of M78 into the virion envelope during the course of virion maturation (Sharp et al. 2009). This protein is a member of the β-herpesvirus 'UL78 family' of seven transmembrane receptors which are required for efficient cell-cell spread of the virus in tissue culture, and M78 knockout viruses are attenuated for replication in vivo. M78 forms dimers, a property common to several cellular 7TMR. It traffics to the cell surface but is rapidly and constitutively endocytosed. In MCMV-infected cells, the subcellular localization of M78 is modified during the course of infection, which may be related to the incorporation of M78 into the virion envelope during the course of virion maturation (Sharp et al. 2009).	Viruses	Heunggongvirae, Peploviricota	M78 of murine cytomegalovirus
9.A.14.18.2	pR78 protein of 474 aas and 7 TMSs.	Viruses	Heunggongvirae, Peploviricota	pR78 of Rat cytomegalovirus
9.A.14.18.3	Envelope protein UL78 of 431 aas and 7 TMSs.	Viruses	Heunggongvirae, Peploviricota	UL78 of Human cytomegalovirus (strain Toledo) (HHV-5) (Human herpesvirus 5)
9.A.14.18.4	Envelope protein U78 of 333 aas and 7 TMSs	Viruses	Heunggongvirae, Peploviricota	UL78 of Saimiriine herpesvirus 4
9.A.14.19.1	G-protein receptor, GPR160 of 338 aas and 8 putative TMSs. The expression level of endogenous GPR160 is associated with the pathogenesis of prostate cancer as well as apoptosis and cell cycle arrest (Zhou et al. 2016).	Eukaryota	Metazoa, Chordata	GPR160 of Homo sapiens
9.A.14.20.1	The Ocular albinism type 1 gene product, OA1, or G-protein coupled receptor 143 (GPR143) of 404 aas and 7 established TMSs (Sone and Orlow 2007). OA1 (GPR143) is a pigment cell-specific intracellular glycoprotein that is mutated in patients with ocular albinism type 1, the most common form of ocular albinism. Its cellular localization appears to be endolysosomal and melanosomal. It is a receptor for tyrosine, L-DOPA and dopamine. Binding of L-DOPA stimulates Ca²⁺ influx into the cytoplasm, increases secretion of the neurotrophic factor SERPINF1 and relocalizes beta arrestin at the plasma membrane; this ligand-dependent signaling occurs through a G(q)-mediated pathway in melanocytic cells. Its activity is mediated by G proteins which activate the phosphoinositide signaling pathway. It also plays a role as an intracellular G protein-coupled receptor involved in melanosome biogenesis, organization and transport (Palmisano et al. 2008; Giordano et al. 2009).	Eukaryota	Metazoa, Chordata	OA1 of Homo sapiens
9.A.14.21.1	The G-protein-coupled bile acid receptor of 330 aas and 7 TMSs, GPCR19. Bile acid-binding induces its internalization, activation of extracellular signal-regulated kinase and intracellular cAMP production. May be involved in the suppression of macrophage functions by bile acids (Maruyama et al. 2002; Kawamata et al. 2003; Häussinger and Kordes 2017).	Eukaryota	Metazoa, Chordata	GPCR19 of Homo sapiens
9.A.14.22.1	Putative G-protein receptor, GPCR, of 505 aas and 7 TMSs.	Eukaryota	Oomycota	GPCR of Phytophthora sojae (Soybean stem and root rot agent) (Phytophthora megasperma f. sp. glycines)
9.A.14.22.2	Putative G-protein receptor of 600 aas and 7 TMSs, GPR107. It has been proposed to act as a receptor for neuronostatin, a peptide derived from the somatostatin/SST precursor (Yosten et al. 2012). It is also involved in blood sugar regulation through the induction of glucagon in response to low glucose. It is required for intoxication by Pseudomonas aeruginosa exotoxin A and Campylobacter jejuni CDT. It may also contribute to the retrograde transport of bacterial toxins, including cholera toxin, from the trans-Golgi network to the endoplasmic reticulum (Tafesse et al. 2014).	Eukaryota	Metazoa, Chordata	GPR107 of Homo sapiens
9.A.14.22.3	Uncharacterized protein, putative G-protein receptor of 421 aas and 7 TMSs.	Eukaryota	Evosea	UP of Entamoeba histolytica
9.A.14.22.4	TMEM87A of 555 aas and 7 TMSs. It may be involved in retrograde protein transport from endosomes to the trans-Golgi network (TGN) (Hirata et al. 2015). TMEM87s are eukaryotic transmembrane proteins with two members (TMEM87A and TMEM87B) in humans. TMEM87s have proposed roles in protein transport to and from the Golgi, as mechanosensitive ion channels, and in developmental signaling. TMEM87 disruption has been implicated in cancers and developmental disorders. Hoel et al. 2022 determined a cryo-EM structure of human TMEM87A in lipid nanodiscs. TMEM87A consists of a Golgi-dynamics (GOLD) domain atop a membrane-spanning seven-TMS domain with a large cavity open to solution and the membrane outer leaflet. Structural and functional analyses suggested that TMEM87A may not function as an ion channel or G-protein coupled receptor. They found that TMEM87A shares its characteristic domain arrangement with seven other proteins in humans; three that had been identified as evolutionary related (TMEM87B, GPR107, and GPR108) and four previously unrecognized homologs (GPR180, TMEM145, TMEM181, and WLS). Among these structurally related GOLD domain seven-TMS (GOST) proteins, WLS is best characterized as a membrane trafficking and secretion chaperone for lipidated Wnt signaling proteins. Key structural determinants for WLS function are conserved in TMEM87A. Hoel et al. 2022 proposed that TMEM87A and structurally homologous GOST proteins could serve a common role in trafficking membrane-associated cargo. According to Chakrabarti et al. 2024, touch sensation requires the mechanically gated ion channel ELKIN1.	Eukaryota	Metazoa, Chordata	TMEM87A of Homo sapiens
9.A.14.22.5	TMEM87B of 555 aas and 7 TMSs. It is the same length and topology with 49% identity to TMEM87A. It may be involved in retrograde transport from endosomes to the trans-Golgi network (TGN) (Hirata et al. 2015).	Eukaryota	Metazoa, Chordata	TMEM87B of Homo sapiens
9.A.14.22.6	GPR108 of 543 aas and 7 TMSs. It may play a role in intracellular immune modulation by activating the NF-kappaB response and attenuating the Toll-like-receptor response. It also plays an essential function in adeno-associated virus (AAV) transduction across multiple serotypes except AAV5. It may play a critical role in mediating the endosomal virus escape or in the AAV virions trafficking from endosomes to the nucleus (Dudek et al. 2020).	Eukaryota	Metazoa, Chordata	GPR108 of Homo sapiens
9.A.14.23.1	Serpentine receptor, class alpha-6 (α6) of 329 aas and 7 TMSs, Sra-6. Chemoreception is mediated in Caenorhabditis elegans by members of the seven-transmembrane G-protein-coupled receptor class (7TMS GPCRs) of proteins which are of the serpentine type. Sra is part of the Sra superfamily of chemoreceptors. Chemoperception is one of the central senses of soil nematodes like C. elegans which are otherwise 'blind' and 'deaf'.	Eukaryota	Metazoa, Nematoda	Sra of Caenorhabditis elegans
9.A.14.23.2	Serpentine Receptor, class AB (class A-like) of 331 aas and 7 TMSs.	Eukaryota	Metazoa, Nematoda	SraR, class AB of Caenorhabditis elegans
9.A.14.23.3	Serpentine Receptor, class B (beta) of 350 aas and 7 TMSs.	Eukaryota	Metazoa, Nematoda	Sra-B of Caenorhabditis elegans
9.A.14.23.4	Uncharacterized serpentine receptor of 336 aas and 7 TMSs.	Eukaryota	Metazoa, Nematoda	Receptor of Caenorhabditis elegans
9.A.14.23.5	Serpentine receptor class alpha/beta-14 of 280 aas and 7 TMSs.	Eukaryota	Metazoa, Nematoda	SraA14 of Toxocara canis
9.A.14.23.6	Uncharacterized protein of 334 aas and 7 TMSs.	Eukaryota	Metazoa, Nematoda	UP of Ancylostoma ceylanicum
9.A.14.23.7	Uncharacterized protein of 575 aas and 7 TMSs.	Eukaryota	Metazoa, Nematoda	UP of Caenorhabditis elegans
9.A.14.23.8	Serpentine receptor class alpha-9, Sra-9, of 331 aas and 7 TMSs. It belongs to a chemosensory gene family, the serpentine receptor class ab (srab), which exists with 25 members in C. elegans and 14 members in C. briggsae (Chen et al. 2005). Sra-9 and Nlp-26 are required for polarized epidermal growth factor (EGF) secretion (Mereu et al. 2020).		Metazoa, Nematoda	Sra-9 of Caenorhabditis elegans
9.A.14.24.1	Serpentine receptor class r-10, Odr10, of 339 aas and 7 TMSs. It is an odorant receptor which affects chemotaxis to the volatile odorant diacetyl (Sengupta et al. 1996). It specifies AWA neuronal cell fate via the odr-7 pathway (Sagasti et al. 1999).	Eukaryota	Metazoa, Nematoda	Odr10 of Caenorhabditis elegans
9.A.14.24.2	Chemoreceptor of 349 aas and 7 TMSs.	Eukaryota	Metazoa, Nematoda	Chemoreceptor of Ancylostoma ceylanicum
9.A.14.24.3	G protein-coupled receptor of 463 aas and 7 TMSs.	Eukaryota	Metazoa, Nematoda	GPCR of Pristionchus pacificus
9.A.14.24.4	Chemoreceptor of 386 aas and 7 TMSs.	Eukaryota	Metazoa, Nematoda	Chemoreceptor of Ancylostoma duodenale
9.A.14.24.5	Uncharacterized protein of 547 aas and 7 TMSs.	Eukaryota	Metazoa, Nematoda	UP of Diploscapter pachys
9.A.14.24.6	GPCR, serpentine receptor class j (Srj) family-containing protein of 333 aas and 7 TMSs.		Metazoa, Nematoda	GPCR of Strongyloides ratti
9.A.14.24.7	Str-19 of 344 aas and 7 TMSs.	Eukaryota	Metazoa, Nematoda	Str-19 of Bursaphelenchus xylophilus (pine wood nematode)
9.A.14.25.1	Uncharacterized protein of 237 aas and 7 TMSs	Archaea	Candidatus Lokiarchaeota	UP of Candidatus Prometheoarchaeum syntrophicum
9.A.14.25.2	Uncharacterized protein of 239 aas and 7 TMSs.	Archaea	Candidatus Lokiarchaeota	UP of Candidatus Lokiarchaeota archaeon (sediment metagenome)
9.A.14.25.3	Uncharacterized protein of 247 aas and 7 TMSs.	Archaea	Candidatus Heimdallarchaeota	UP of Candidatus Heimdallarchaeota archaeon (marine sediment metagenome)
9.A.14.26.1	Integral membrane protein, GPR180, of 698 aas and 8 probable TMSs with one at the N-terminus and 7 at the C-terminus. This C-terminal domain is homologous to other proteins in this family. This G-protein-coupled receptor modulates gametogenesis via the PKG-mediated signaling cascade in Plasmodium berghei (Wang et al. 2022). Functional conservation of GPR180s in other Plasmodium spp. has been demonstrated (Wang et al. 2022).	Eukaryota	Apicomplexa	GPR180 of Plasmodium falciparum
9.A.14.26.2	Tmem145 of 843 aas and 8 TMSs in a 1 (N-terminal) + 7 (C-terminal) TMS arrangement. Although this protein resembles that with TC# 9.B.14.8.1, only the C-terminal membrane domain is similar.	Eukaryota		Tmem145 of Symbiodinium natans
9.A.14.26.3	Integral membrane protein, GPR180-like, of 422 aas and 8 TMSs, one N-terminal, and 7 C-terminal.	Eukaryota	Metazoa, Porifera	GPR180 of Amphimedon queenslandica
9.A.14.26.4	TMEM145 of 493 aas and 7 TMSs. It is a G-protein-coupled receptor (Hoel et al. 2022).	Eukaryota	Metazoa, Chordata	TMEM145 of Homo sapiens