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1.A.9.1.1
Nicotinic acetylcholine-activated cation-selective channel, pentameric α2βγδ (immature muscle) nα2βγδ (mature muscle), is activated by nicotine (Shen et al. 2022). A  combination of symmetric and asymmetric motions opens the gate, and the asymmetric motion involves tilting of the TM2 helices (Szarecka et al. 2007). Acetylcholine receptor δ subunit mutations underlie a fast-channel myasthenic syndrome and arthrogryposis multiplex congenita (Brownlow et al., 2001; Webster et al., 2012). Residues in TMS2 and the cytoplasmic loop linking TMSs 3 and 4 influence conductance, selectivity, gating and desensitization (Peters et al., 2010). nAChR and TRPC channel proteins (1.A.4) mediate nicotine addiction in many animals from humans to worms (Feng et al., 2006). Cholesterol recognition motifs in transmembrane domains of the human nicotinic acetylcholine receptor have been identified (Baier et al., 2011). Allosteric modulators of the α4β2 subtype of neuronal nicotinic acetylcholine receptors, the dominant type in the brain, are numerous (Pandya and Yakel, 2011).  α2β2 and α4βnicotinic acetylcholine receptors are inhibited by the β-amyloid(1-42) peptide (Pandya and Yakel, 2011b).  The A272E mutation in the alpha7 subunit gives rise to spinosad insensitivity without affecting activation by acetylcholine (Puinean et al. 2012). Inhibited by general anaesthetics (Nury et al., 2011). The X-ray crystal structures of the extracellular domain of the monomeric state of human neuronal alpha9 nicotinic acetylcholine receptor (nAChR) and of its complexes with the antagonists methyllycaconitine and alpha-bungarotoxin have been determined at resolutions of 1.8 A, 1.7 A and 2.7 A, respectively (Zouridakis et al. 2014).  Structurally similar allosteric modulators of α7 nAChR exhibit five different pharmacological effects (Gill-Thind et al. 2015).  Mutations causing slow-channel myasthenia show that a valine ring in the channel is optimized for stabilizing gating (Shen et al. 2016).  Quinoline derivatives act as agonists or antagonists depending on the type and subunit (Manetti et al. 2016). Conformational changes stabilize a twisted extracellular domain to promote transmembrane helix tilting, gate dilation, and the formation of a ""bubble"" that collapses to initiate ion conduction (Gupta et al. 2016). A high-affinity cholesterol-binding domain has been proposed for this and other ligand-gated ion channels (Di Scala et al. 2017). Positive allosteric modulators have been identified (Deba et al. 2018). Menthol stereoisomers exhibit fifferent effects on alpha4beta2 nAChR upregulation and dopamine neuron spontaneous firing (Henderson et al. 2019). Corticosteroids exert direct inhibitory action on the muscle-type AChR (Dworakowska et al. 2018). Both deltaL273F and epsilonL269F mutations impair channel gating by disrupting hydrophobic interactions with neighboring alpha-subunits. Differences in the extent of impairment of channel gating in delta and epsilon mutant receptors suggest unequal contributions of epsilon/alpha and delta/alpha subunit pairs to gating efficiency (Shen et al. 2019). Diffusion dynamics of the gangliosides, GM1s and AChRs is uniformly affected by the intracellular ATP level of a living muscle cell (He et al. 2020). M4, the outermost helix, is involved in opening of the alpha4beta2 nACh receptor (Mesoy and Lummis 2020). Cholesterol modulates the organization of the gammaM4 transmembrane domain of the muscle nicotinic acetylcholine receptor (de Almeida et al. 2004). Cryo-EM images showed that cholesterol segregates preferentially around the constituent ion channel of the  receptor, interacting with specific sites in both leaflets of the bilayer. Cholesterol forms microdomains - bridges of rigid sterol groups that link one channel to the next (Unwin 2021).  Desnitro-imidacloprid (DN-IMI) functionally affects human neurons similarly to the well-established neurotoxicant nicotine by triggering activation of alpha7 and several non-alpha7 nAChRs (Loser et al. 2021). The "lipid sensor" ability displayed by the outer ring of the M4 TMS and its modulatory role on nAChR function have been reviewed (Barrantes 2023).  Anesthetic and two neuromuscular blockers act on muscle-type nicotinic receptors; the intravenous anesthetic etomidate binds at an intrasubunit site in the transmembrane domain and stabilizes a non-conducting, desensitized-like state of the channel (Goswami et al. 2023). The depolarizing neuromuscular blocker succinylcholine also stabilizes a desensitized channel but does so through binding to the classical neurotransmitter site. Rocuronium binds in this same neurotransmitter site but locks the receptor in a resting, non-conducting state.  A novel binding site in the nicotinic acetylcholine receptor for MB327 can explain its allosteric modulation relevant for organophosphorus-poisoning treatment (Kaiser et al. 2023). A recombinant cellular model system for human muscle-type nicotinic acetylcholine receptor (alpha1(2)beta1deltaepsilon) has been presented (Brockmöller et al. 2023). AChR has 2 orthosteric sites (for neurotransmitters) in the extracellular domain linked to an allosteric site (a gate) in the transmembrane domain (Auerbach 2024).

Accession Number:Q07001
Protein Name:Acetylcholine receptor subunit delta
Length:517
Molecular Weight:58895.00
Species:Homo sapiens (Human) [9606]
Number of TMSs:4
Location1 / Topology2 / Orientation3: Cell junction1 / Multi-pass membrane protein2
Substrate inorganic cation

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FASTA formatted sequence
1:	MEGPVLTLGL LAALAVCGSW GLNEEERLIR HLFQEKGYNK ELRPVAHKEE SVDVALALTL 
61:	SNLISLKEVE ETLTTNVWIE HGWTDNRLKW NAEEFGNISV LRLPPDMVWL PEIVLENNND 
121:	GSFQISYSCN VLVYHYGFVY WLPPAIFRSS CPISVTYFPF DWQNCSLKFS SLKYTAKEIT 
181:	LSLKQDAKEN RTYPVEWIII DPEGFTENGE WEIVHRPARV NVDPRAPLDS PSRQDITFYL 
241:	IIRRKPLFYI INILVPCVLI SFMVNLVFYL PADSGEKTSV AISVLLAQSV FLLLISKRLP 
301:	ATSMAIPLIG KFLLFGMVLV TMVVVICVIV LNIHFRTPST HVLSEGVKKL FLETLPELLH 
361:	MSRPAEDGPS PGALVRRSSS LGYISKAEEY FLLKSRSDLM FEKQSERHGL ARRLTTARRP 
421:	PASSEQAQQE LFNELKPAVD GANFIVNHMR DQNNYNEEKD SWNRVARTVD RLCLFVVTPV 
481:	MVVGTAWIFL QGVYNQPPPQ PFPGDPYSYN VQDKRFI