1.A.8 The Major Intrinsic Aquaporin Protein, (MIP) Family
The Major Intrinsic Protein (MIP) of the human lens of the eye (Aqp0), after which the MIP family was named, represents about 60% of the protein in the lens cell. In the native form, it is an aquaporin, but during lens development, it becomes proteolytically truncated. The channel, which normally houses 6-9 water molecules, becomes constricted so only three remain, and these are trapped in a closed conformation (Gonen et al., 2004a,b). These truncated tetramers form intercellular adhesive junctions (head to head), yielding a crystalline array that mediates lens formation with cells tightly packed as required to form a clear lens (Gonen and Walz, 2006). Aquaporin ion conductance properties are defined by the membrane environment, the protein structure, and the cell physiology (Henderson et al. 2022). Aqps in some organisms have been the subject of studies such as ticks. Gene expression of AQPs in different tick tissues and stages showed the highest expression levels in salivary glands and gut of adult female Haemaphysalis qinghaiensis. (Niu et al. 2022). AQPs are differentially expressed in various cardiovascular tissues of humans and participate in water transmembrane transport, cell migration, metabolism, and inflammatory responses (Shangzu et al. 2022). AQP1, AQP2, AQP4, AQP5, and AQP8 are primarily water selective, whereas AQP3, AQP7, AQP9, and AQP10 (called 'aqua-glyceroporins') also transport glycerol and other small solutes. AQPs play roles in cancer cell growth, migration, invasion, and angiogenesis (Moon et al. 2022). In the bivalve, the invasive freshwater mussel Dreissena rostriformis, midbody-localized aquaporin mediates intercellular lumen expansion during early cleavage (Zieger et al. 2022). Aqp-mediated water distributions' in astrocytes under normal and pathological conditions have been reviewed (Zhou et al. 2022). Several methods have been developed for the measurement of water permeability, both in living cells and in tissues (Solenov et al. 2023). The importance of aquaporins in fetal developmenthas been reviewed (Martínez and Damiano 2023). The biological functions of AQPs are regulated by posttranslational modifications, e.g., phosphorylation, ubiquitination, glycosylation, subcellular distribution, degradation and protein interactions (Xiong et al. 2023). dbAQP-SNP is a database of missense single-nucleotide polymorphisms in human aquaporins (Dande and Sankararamakrishnan 2023). Raza et al. 2023 unveiled the complete genomic atlas of aquaporins across the genus Oryza. The genome-wide identification and gene expression analysis of sweet cherry aquaporins (Prunus avium L.) under abiotic stresses have been reported (Salvatierra et al. 2023). The genome-wide identification of Aqp family members related to spermatogenesis in turbot (Scophthalmus maximus) has been achieved (Wang et al. 2023). Plasma membrane aquaporins of the PIP1 and PIP2 subfamilies facilitate hydrogen peroxide diffusion into plant roots (Israel et al. 2022). Roles of AQPs in epilepsy and seizure onset in humans have been discussed and reviewed (Bonosi et al. 2023).
Lipids crystallize with the protein (Gonen et al., 2005). Ion channel activity has been shown for Aquaporins 0, 1, and 6, Drosophila Big Brain and plant Nodulin-26 (Yool and Campbell, 2012). Roles of aquaporins in human cancer have been reviewed (Pareek et al. 2013) as have their folding pathways (Klein et al. 2015). AQPs may act as transmembrane osmosensors in red cells, secretory granules and microorganisms (Hill and Shachar-Hill 2015). MIP superfamly proteins and variations of their selectivity filters have been reviewed (Verma et al. 2015). Their evolution has been discussed (Ishibashi et al. 2017). AQPs have a variety of functions and are related to inner ear diseases such as Meniere's disease, sensorineural hearing loss, and presbycusis (Dong et al. 2019). AQPs are also important for male reproductive health (Carrageta et al. 2019). The evolution of the aquaporin superfamily has been discussed (Ishibashi et al. 2020). The cellular functions of aquaporins are regulated mainly by posttranslational modifications, e.g., phosphorylation, ubiquitination, glycosylation, subcellular distribution, degradation, and protein interactions (Li et al. 2020). Aquaporins play roles in inflammation (Mariajoseph-Antony et al. 2020) and in various aspects of health and disease (Magouliotis et al. 2020). They play major roles in secretion of saliva by salivary glands, and their disruption can cause a variety of diseases (D'Agostino et al. 2020). Aquaporins in mamalian lungs have been reviewed (Yadav et al. 2020). Lineage-level divergence of copepod glycerol transporters and the emergence of isoform-specific trafficking regulation has been documented (Catalán-García et al. 2021). Aquaporins play key roles in fluid homeostasis, glandular secretions, signal transduction and sensation, barrier function, immunity and inflammation, cell migration, and angiogenesis (Wagner et al. 2022). Aquaporins are gated, opening and closing to control water permeation (Ozu et al. 2022). They play roles in breast cancer progression and treatment (Charlestin et al. 2022). The function of aquaporins in gastrointestinal fluid absorption and secretion have been discussed (Calamita and Delporte 2023).
The MIP family is large and diverse, possessing thousands of members that form transmembrane channels. These channel proteins function in water, small carbohydrate (e.g., glycerol), urea, NH3, CO2, H2O2 and ion transport by energy-independent mechanisms. For example, the glycerol channel, FPS1p of Saccharomyces cerevisiae mediates uptake of arsenite and antimonite (Wysocki et al., 2001). Ion permeability appears to occur through a pathway different than that used for water/glycerol transport and may involve a channel at the 4 subunit interface rather than the channels through the subunits (Saparov et al., 2001). MIP family members are found ubiquitously in bacteria, archaea and eukaryotes. Phylogenetic clustering of the proteins is largely according to phylum of the organisms of origin, but one or more clusters are observed for each phylogenetic kingdom (plants, animals, yeast, bacteria and archaea) (Park and Saier, 1996). MIPs are classified into five subfamilies in higher plants, including plasma membrane (PIPs), tonoplast (TIPs), NOD26-like (NIPs), small basic (SIPs) and unclassified X (XIPs) intrinsic proteins. One of the plant clusters includes only tonoplast (TIP) proteins, while another includes plasma membrane (PIP) proteins (de Paula Santos Martins et al. 2015). Aquaporins in Nicotiana tabacum have been tabulated, and their relationships to other Solanaceae species have been described (De Rosa et al. 2020). A genome analysis of Betula pendula (silver birch) identified 33 putative genes encoding full-length AQP sequences (BpeAQPs). They are grouped into five subfamilies, representing ten plasma membrane intrinsic proteins (PIPs), eight tonoplast intrinsic proteins (TIPs), eight NOD26-like intrinsic proteins (NIPs), four X intrinsic proteins (XIPs), and three small basic intrinsic proteins (SIPs) (Venisse et al. 2021). Fungal X-intrinsic protein aquaporins from Trichoderma atroviride have been studied (Amira et al. 2021). In the parasidic helminthes, AQPs play roles in promoting the transport of water, osmoregulation, uptake of nutrients, release of toxic metabolic products and transport of antiparasitic drugs (Wang and Ye 2020). Their involvement in diseases pathogenesis has been reviewed (Ala et al. 2021). In humans, AQP3, AQP7, AQP9, and AQP10, play critical roles in cancer. Overexpression or knockdown of AQGPs can promote or inhibit cancer cell proliferation, migration, invasion, apoptosis, epithelial-mesenchymal transition and metastasis, and the expression levels of AQGPs are closely linked to the prognosis of cancer patients. The expression patterns of AQPs in different cancers as well as the relationship between the expression patterns and prognosis have been reviewed (Wang et al. 2022). The role of AQP5 in the biology of lung adenocarcinoma as well as its prognostic value have been reviewed (Jaskiewicz et al. 2023).
The known aquaporins cluster loosely together on a pylogenetic tree as do the known glycerol facilitators. MIP family proteins are believed to form aqueous pores that selectively allow passive transport of their solute(s) across the membrane with minimal apparent recognition. Aquaporins selectively transport water (but not glycerol) while glycerol facilitators selectively transport glycerol but not water. Some aquaporins can transport NH3 and CO2. Glycerol facilitators function as solute nonspecific channels, and may transport glycerol, dihydroxyacetone, propanediol, urea and other small neutral molecules in physiologically important processes. Some members of the family, including the yeast Fps1 protein (TC #1.A.8.5.1) and tobacco NtTIPa (TC #1.A.8.10.2) may transport both water and small solutes. A constriction within the pore, the aromatic/arginine (ar/R) selectivity filter, is thought to control solute permeability: narrow channels conduct water, whilst wider channels permit passage of solutes. Substrate discrimination depends on a complex interplay between the solute, pore size, and polarity (Kitchen et al. 2019). Brain fluid can be secreted against an osmotic gradient, suggesting that conventional osmotic water flow via aquaporins may not fully describe transmembrane fluid transport in the brain (MacAulay 2021). Aquaporins are essential to maintain motility and membrane lipid architecture during mammalian sperm capacitation (Delgado-Bermúdez et al. 2021). The effects of Aloe-Emodin on the expression of brain aquaporins and secretion of neurotrophic factors has been reported (Liu et al. 2023).
Calamita et al. 2018 review the expression, regulation and physiological roles of AQPs in adipose tissue, liver and endocrine pancreas that are involved in energy metabolism. The review also summarizes the involvement of AQPs in metabolic disorders, such as obesity, diabetes and liver diseases. Challenges and recent advances related to pharmacological modulation of AQPs expression and function to control and treat metabolic diseases are discussed (Calamita et al. 2018). Jain et al. 2018 have shown that an intra-helical salt-bridge in the Loop E half-helix can influence the transport properties of AQP1 and GlpF channels. AQPs are homotetramers with two conserved asparagine-proline-alanine (NPA) motifs embedding in the plasma membrane. The cellular functions of aquaporins are regulated mainly by posttranslational modifications, e.g., phosphorylation, ubiquitination, glycosylation, subcellular distribution, degradation, and protein interactions. Aquaporins, in particular, AQP2, play important roles in some disease conditions such as water loss and gain (Li et al. 2020). The expression of AQP-1, -3, -4, -5, -8 and -9 were documented in the digestive system, where these six AQP isoforms serve essential roles including mediating the transmembrane water transport and regulating the secretion of gastrointestinal (GI) fluids, consequently facilitating the digestion and absorption of GI contents (Liao et al. 2021). The expression levels of AQPs are controlled by various factors, and AQPs can stimulate various signaling pathways; however, aberrant expression of AQPs in the GI tracts are associated with the initiation and development of numerous diseases (Liao et al. 2021). Altered iris aquaporin expression and aqueous humor osmolality in glaucoma have been compared (Huang et al. 2021).
Zardoya and Villalba (2001) have conducted phylogenetic analyses of the MIP family, analyzing 153 homologues. They divided the proteins into six major 'paralogous' groups: (1) GLPs, or glycerol-transporting channel proteins, which include mammalian AQP3, AQP7, and AQP9, several nematode paralogues, a yeast paralogue, and Escherichia coli GLP; (2) AQPs, or aquaporins, which include metazoan AQP0, AQP1, AQP2, AQP4, AQP5, and AQP6; (3) PIPs, or plasma membrane intrinsic proteins of plants, which include PIP1 and PIP2; (4) TIPs, or tonoplast intrinsic proteins of plants, which include αTIP, γTIP, and δTIP; (5) NODs, or nodulins of plants; and (6) AQP8s, or metazoan aquaporin 8 proteins. Of these groups, AQPs, PIPs, and TIPs cluster together as noted above. Wild and domesticated olive species have 52 and 79 genes encoding full-length AQP sequences, respectively (Faize et al. 2020). They fall into five established subfamilies: PIP, TIP, NIP, SIP, and XIP and their substrate specificities and cellular localizations were predicted (Faize et al. 2020). AQPs' selectivities are not exclusively shaped by pore-lining residues but are also determined by the relative arrangement of transmembrane helices (Gössweiner-Mohr et al. 2022). Aquaporins in astrocytes have been reviewed (Zhou et al. 2022). The diverse range of substrates conducted by aquaporin family members, particularly those of human origin, have been reviewed (Sachdeva et al. 2022), and current knowledge of the AQP interactomes and the molecular basis and functional significance of these protein-protein interactions in health and diseases have also been reviewed (Törnroth-Horsefield et al. 2022). Aquaporins in the digestive system have similarly been reviewed (Ye et al. 2023). Their functions and mechanisms have also been reviewed (Calamita 2023).
In agreement with their divergent sequences, human AQP1-9 have very different physiological functions. They are involved in (1) nephrogenic diabetes insipidus, (2) brain water balance and hearing and (3) salivary secretion (Li and Verkman, 2001). Bacterial homologues also have diverse functions. Two proteins in E. coli function as water and glycerol transporters, respectively. Lactobacillus plantarum has 6 homologues, some of which transport water, glycerol and dihydroxyacetone, and some which transporter these compounds as well as D,L-lactic acid (Bienert et al. 2013). The pH sensitivities of Aqp0 channels in lenses of tetraploid and diploid teleosts have been reported (Chauvigné et al. 2015). In the heart, AQPs are implicated in proper cardiac water homeostasis and energy balance as well as heart failure and arsenic cardiotoxicity (Verkerk et al. 2019). Because of their glycerol permeability, aquaglyceroporins are involved in energy homeostasis. Calamita and Delporte 2021 provided an overview of the functional implication and control of aquaglyceroporins in tissues involved in energy metabolism, i.e. liver, adipose tissue and the endocrine pancreas. The expression, role and (dys)regulation of aquaglyceroporins in disorders affecting energy metabolism is also addressed. Aquaporins (AQPs) are involved in autoimmune diseases including neuromyelitis optica, Sjogren's syndrome and rheumatoid arthritis. Both autoantibodies against AQPs and altered expression and/or trafficking of AQPs in various tissue cell types as well as inflammatory cells play key roles in pathogenesis of autoimmune diseases. Detection of autoantibodies against AQP4 in the central nervous system has paved the way for a deeper understanding in disease pathophysiology (Delporte and Soyfoo 2022).
Several reports of MIP family proteins transporting ions may or may not be physiologically significant. For example, the influx of arsenite and antimonite via the Fps1 protein into yeast cells is well documented (Wysocki et al., 2001). Similarly, these compounds are taken up via aquaporins in Leishmania (Gourbal et al., 2004). Moreover, AQP6 of renal epithelia have been reported to transport anions at low pH (Yasui et al., 1999). Demonstration of the involvement of the cyanobacterial channel protein (TC #1.A.8.4.1) in copper homeostasis suggests that it may transport Cu2+. Finally, Yang et al. (2005) showed that arsenite exists the Mesorhizobium meliloti cell by downhill movement through AqpS (1.A.8.15.1). The physiological functions of many MIP family proteins are unknown. Differential expression of aquaporin genes and the influence of environmental hypertonicity on their expression in juveniles of air-breathing stinging catfish (Heteropneustes fossilis) has been examined (Chutia et al. 2022). The results show that AQPs play crucial roles in maintaining the water and ionic balances under anisotonic conditions, even at the early developmental stages of stinging catfish. In humans, AQP1 is present in myoepithelial cells and in endothelial cells of small blood vessels; AQP3 shows basolateral plasmamembrane localization in glandular endpieces, and AQP5 is localized at the apical cytomembrane in serous and mucous glandular cells and at the lateral membrane in serous cells (Stoeckelhuber et al. 2023).
MIP family channels consist of homotetramers (e.g., GlpF of E. coli; TC #1.A.8.1.1, AqpZ of E. coli; TC #1.A.8.3.1, and MIP or Aqp0 of Bos taurus; TC #1.A.8.8.1). Each subunit spans the membrane six times as putative α-helices and arose from a 3-spanner-encoding genetic element by a tandem, intragenic duplication event. The two halves of the proteins are therefore of opposite orientation in the membrane. However, a well-conserved region between TMSs 2 and 3 and TMSs 5 and 6 dip into the membrane, each loop forming a half TMS. A voltage-related gating mechanism involving the conserved arginine of the channel's main constriction was captured for human aquaporins through molecular dynamics studies. Mom et al. 2020 showed that this voltage-gating is probably conserved among members of this family and that the underlying mechanism may explain part of plant AQPs diversity when contextualized to high ionic concentrations provoked by drought.
Several MIPs within all domains of life have been shown to facilitate the diffusion of reduced and non-charged species of the metalloids silicon, boron, arsenic and antimony (Bienert et al., 2008). Metalloids encompass a group of biologically important elements ranging from the essential to the highly toxic. Consequently, all organisms require efficient membrane transport systems to control the exchange of metalloids with the environment. Genetic evidence has demonstrated a crucial role for specific MIPs in metalloid homeostasis (Bienert et al., 2008). Permeation through each monomer of a tetrameric Aqp is consistent with closed and open states, introducing the term 'gating mechanism' into the field (Ozu et al. 2022).
The crystal structure of the glycerol facilitator of E. coli was solved at 2.2 Å resolution (Fu et al., 2000). Glycerol molecules line up in single file within the amphipathic channel. In the narrow selectivity filter of the channel, the glycerol alkyl backbone is wedged against a hydrophobic corner, and successive hydroxyl groups form hydrogen bonds with a pair of acceptor and donor atoms. The two conserved D-P-A motifs in the loops between TMSs 2 and 3 and TMSs 5 and 6 form the interface between the two duplicated halves of each subunit. Thus each half of the protein forms 3.5 TMSs surrounding the channel. The structure explains why GlpF is selectively permeable to straight chain carbohydrates, and why water and ions are excluded. Aquaporin-1 (AQP1) and the bacterial glycerol facilitator, GlpF can transport O2, CO2, NH3, glycerol, urea, and water to varying degrees. For small solutes permeating through AQP1, a remarkable anticorrelation between permeability and solute hydrophobicity was observed whereas the opposite trend was observed for permeation through the membrane (Hub and Groot, 2008). AQP1 is thus a selective filter for small polar solutes, whereas GlpF is highly permeable to small solutes and less permeable to larger solutes.
Aquaporin-1 (Aqp1) from the human red blood cell has been solved by x-ray crystallography to 3.8 Å resolution (Murata et al., 2000). The aqueous pathway is lined with conserved hydrophobic residues that permit rapid water transport. Water selectivity is due to a constriction of the inner pore diameter to about 3 Å over the span of a single residue, superficially similar to that in the glycerol facilitator of E. coli. The role of aquaporins in corneal healing post chemical injury has been described (Bhend et al. 2023).
AqpZ, a homotetramer (tAqpZ) of four water-conducting channels that facilitate rapid water movements across the plasma membrane of E. coli, has been solved to 3.2 Å resolution. All channel-lining residues in the four monomeric channels are found orientated in nearly identical positions with one marked exception at the narrowest channel constriction, where the side chain of a conserved Arg-189 adopts two distinct conformational orientations. In one of the four monomers, the guanidino group of Arg-189 points toward the periplasmic vestibule, opening up the constriction to accommodate the binding of a water molecule through a tridentate H-bond. In the other three monomers, the Arg-189 guanidino group bends over to form an H-bond with carbonyl oxygen of Thr-183 occluding the channel. Therefore, the tAqpZ structure reveals two distinct Arg-189 conformations associated with water permeation through the channel constrictions. Alternating between the two Arg-189 conformations disrupts continuous flow of water, thus regulating the open probability of the water pore. Further, the difference in Arg-189 displacements is correlated with a strong electron density found between the first transmembrane helices of two open channels, suggesting that the observed Arg-189 conformations are stabilized by asymmetrical subunit interactions in tAqpZ (Jiang et al., 2006).
Plants exhibits high diversity in aquaporin isoforms and broadly classified into five different subfamilies on the basis of phylogenetic distribution and subcellular occurrence: plasma membrane intrinsic proteins (PIPs), tonoplast intrinsic proteins (TIPs), nodulin 26-like proteins (NIPs), small basic intrinsic proteins (SIPs) and uncharacterized intrinsic proteins (XIPs) (Singh et al. 2020). The gating mechanism of aquaporin channels is regulated by post-translational modifications such as phosphorylation, methylation, acetylation, glycosylation, and deamination. Aquaporin expression and transport functions are also modulated by the various phytohormone-mediated signalling in plants. Combined physiology and transcriptome analyses revealed the role of aquaporins in regulating hydraulic conductance in roots and leaves. Aquaporin activities during solute transport, plant development, abiotic stress response, and plant-microbe symbiosis have been reviewed (Singh et al. 2020).
The 3-D structures of the open and closed forms of plant aquaporins, PIP1 and PIP2, have been solved (Törnroth-Horsefield et al., 2006). In the closed conformation, loop D caps the channel from the cytoplasm and thereby occludes the pore. In the open conformation, loop D is displaced up to 16 Å, and this movement opens a hydrophobic gate blocking the channel entrance from the cytoplasm. These results reveal a molecular gating mechanism which appears conserved throughout all plant plasma membrane aquaporins. In plants it regulates water intake/export in response to water availability and cytoplasmic pH during anoxia (Törnroth-Horsefield et al., 2006).
43 AQP genes were identified in the forage crop Medicago sativa. The MsAQP proteins clustered into four subfamilies based on sequence similarity and phylogenetic relationship, including 17 TIPs, 14 NIPs, 9 PIPs and 3 SIPs (Luo et al. 2022). Analyses on cis-acting elements in the promoter regions of MsAQP genes revealed the presence of multiple and diverse stress-responsive and hormone-responsive cis-acting elements. By analyzing the gene expression data of M. truncatula, ten representative MtAQP genes were responsive to NaCl or drought stress. By analyzing the sequence similarity and phylogenetic relationship, the corresponding ten salt- or drought-responsive AQP genes in M. sativa, including three MsTIPs, three MsPIPs and four MsNIPs. The qPCRs showed that the relative expression levels of these ten MsAQP genes responded differently to NaCl or drought treatment in M. sativa. Most MsAQP genes were preferentially expressed in roots or leaves (Luo et al. 2022).
The MIP superfamily includes three functional subfamilies: aquaporins, aquaglyceroporins and S-aquaporins. (1) The aquaporins (AQPs) are water selective. (2) The aquaglyceroporins are permeable to water, but also to other small uncharged molecules. (3) The third subfamily, with little conserved amino acid sequences around the NPA boxes, include 'superaquaporins' (S-aquaporins).The phylogeny of insect MIP family channels has been published (Finn et al. 2015). The arylsulfonamide AqB011 which selectively blocks the central ion pore of mammalian AQP1 has been shown to impair migration of HT29 colon cancer cells. Traditional herbal medicines are sources of selective AQP1 inhibitors that also slow cancer cell migration (Kourghi et al. 2018).
13 isoforms of mammalian aquaporins (AQP0 - AQP12),are known, nine of which localize to different parts of the renal tubular epithelium. Additional transport functions of renal AQPs (AQP3, AQP6, AQP7 and AQP8) are known. Aquaglyceroporins are most probably key elements in the renal regulation of nitrogen balance and maintenance of the correct pH of body fluids (Michalek 2016). In human sperm, AQP3 and AQP11 are expressed mainly in the tail, AQP7 in the head and AQP8 in the midpiece (Pellavio and Laforenza 2021). AQPs are important for the normal functioning of sperm to ensure normal fertility. AQP3, AQP7 and AQP11 are involved in sperm volume regulation, a key role for fertility because osmoadaptation protects the sperm against swelling and tail bending that could affect sperm motility. AQP8 has a fundamental role in regulating the elimination of hydrogen peroxide, the most abundant reactive oxygen species (ROS), and therefore plays a role in the response to oxidative stress (Pellavio and Laforenza 2021).
Otitis media (OM) refers to inflammatory diseases of the middle ear (ME), regardless of cause or pathological mechanism. The expression of aquaporins (AQPs) in the ME and Eustachian tube (ET) is relevant. Eleven types of AQPs, AQP1 to AQP11, have been found to be expressed in mammalian ME and ET (Jung et al. 2017). The distribution and levels of expression of AQPs depend on the presence or absence of inflammation. Fluid accumulation in the ME and ET is a common mechanism for all types of OM, causing edema in the tissue and inducing inflammation involving various AQPs. The expression patterns of several AQPs, especially AQP1, 4 and 5, may have immunological functions in OM.
Some classes of AQPs conduct ions, glycerol, urea, CO2 , nitric oxide, and other small solutes. Ion channel activity has been demonstrated for mammalian AQPs 0, 1, 6, Drosophila big brain (BIB), soybean nodulin 26, and rockcress AtPIP2;1 (Kourghi et al. 2017). Classification of AQPs into three categories (orthodox AQPs, aquaglyceroporins and superaquaporins) is based on their sequence similarities and substrate selectivities. In the male reproductive tract of mammals, most AQPs (except AQP6 and AQP12) are found in different organs (including testis, efferent ducts and epididymis). AQP1 and AQP9 are the most abundant AQPs in the efferent ducts and epididymis and play a crucial role for the secretion/reabsorption dynamics of luminal fluid during sperm transport and maturation. AQP3, AQP7, AQP8 and AQP11 are the most abundant AQPs in sperm and are involved in the regulation of their volumes, which is required for the differentiation of spermatids into spermatozoa during spermatogenesis, as well as in sperm transit along environments of different osmolality (male and female reproductive tracts). Mounting evidence indicates that AQP3, AQP7 and AQP11 are involved in cryotolerance as well as the sperm response to variations of osmolality and to freeze-thawing procedures (Yeste et al. 2017).
In mammals, aquaporins are subdivided into classical aquaporins that are permeable to water; aquaglyceroporins that are permeable to water, glycerol and urea; peroxiporins that facilitate the diffusion of H2O2 through cell membranes; and so called unorthodox aquaporins. Aquaporins ensure important physiological functions in both exocrine and endocrine pancreas and are involved in pancreatic fluid and insulin secretion. Modification of aquaporin expression and/or subcellular localization may be involved in the pathogenesis of pancreatic insufficiencies, diabetes and pancreatic cancer (Arsenijevic et al. 2019).
Mechanisms that drive the development of multiple inflammatory diseases that occur in the nose and contribute to the process of olfactory recognition of compounds entering the nasal cavity involve the action of water channels such as AQPs. Jung et al. 2020 reviewed the relationship between AQPs and rhinologic conditions, focusing on the current state of knowledge and mechanisms that link AQPs and rhinologic conditions. Key conclusions include the following: (1) Various AQPs are expressed in both nasal mucosa and olfactory mucosa; (2) the expression of AQPs in these tissues is different in inflammatory diseases such as AR or CRS, as compared with that in normal tissues; (3) the expression of AQPs in CRS differs depending on the presence or absence of nasal polyps; and (4) the expression of AQPs in tissues associated with olfaction is different from that in the respiratory epithelium.
Water homeostasis plays a crucial role in different reproductive processes, e.g., oocyte transport, hormonal secretion, completion of successful fertilization, blastocyst formation, pregnancy, and birth (Kordowitzki et al. 2020). Further, aquaporins are involved in the process of spermatogenesis, and they have been reported to be involved in the storage of spermatozoa. Aquaporins are relevant for seveeral physiological functions in the female reproductive system, and they are relevant to different pathologies in the female reproductive system. Four Impatiens walleriana aquaporins: IwPIP1;4, IwPIP2;2, IwPIP2;7 and IwTIP4;1, have been characteerized (Đurić et al. 2021). Drought stress affected the aquaporin expression in I. walleriana leaves, which was up- or downregulated depending on stress intensity. Expression of IwPIP2;7 was the most affected of these four aquaporins. At 15% and 5% soil moisture and recovery from 15% and 5% soil moisture, IwPIP2;7 expression significantly decreased and increased, respectively. Aquaporins IwPIP1;4 and IwTIP4;1 had lower expression than IwPIP2;7, with moderate expression changes in response to drought and recovery, while IwPIP2;2 expression was of significance only in recovered plants (Đurić et al. 2021).
Humans contain 13 AQPs (AQP0-AQP12) which are divided into three sub-classes namely orthodox aquaporin (AQP0, 1, 2, 4, 5, 6, and 8), aquaglyceroporin (AQP3, 7, 9, and 10) and super or unorthodox aquaporin (AQP11 and 12) based on their pore selectivity. They are involved in a wide variety of non-infectious diseases including cancer, renal dysfunction, neurological disorders, epilepsy, skin diseases, metabolic syndrome, and even cardiac diseases. AQPs can be regulated by microbial and parasitic infections that suggest their involvement in microbial pathogenesis, inflammation-associated responses and AQP-mediated cell water homeostasis. In a review, Azad et al. 2021 examine the involvement of AQPs in infectious and non-infectious diseases and potential AQPs-target modulators. AQP structures, tissue-specific distributions and physiological relevance, functional diversity and regulation were considered. Human AQPs play roles in edema, glaucoma, nephrogenic diabetes insipidus, oxidative stress, sepsis, cancer, and metabolic dysfunctions (da Silva et al. 2022). The 13 AQPs draw cell lineage-specific expression patterns related to cell native functions. Compelling evidence indicates that AQPs have potential as biomarkers and targets for therapeutic intervention. AQP9 is most expressed in the liver, influencing general metabolic and redox balance due to its aquaglyceroporin and peroxiporin activities. AQP9 levels in other tissues are altered in several human diseases, such as liver injury, inflammation, cancer, infertility, and immune disorders (da Silva et al. 2022). Aqp activities are sensitive to mercury ions (Hg2+). While most aquaporins are inhibited by Hg2+, several are activated. Xie et al. 2022 investigated AqpZ of E. coli (TC# 1.A.8.3.1) inhibition and human AQP6 (TC# 1.A.8.8.4) activation. Based on the structure of the Hg-AqpZ complex, they found that pore closure was caused by mercury-induced conformational changes of the key residue R189 in the selectivity filter region, while pore opening was caused by conformational changes of residues H181 and R196 in the selectivity filter region in AQP6. Both conformational changes were caused by the disruption of the H-bond network of R189/R196 by mercury (Xie et al. 2022).
The generalized transport reaction for channel proteins of the MIP family is:
Reversible H2O (out) → H2O (in) (e.g., aquaporins)
Reversible solute (out) → solute (in) (e.g., glycerol or H2O2 facilitators).
Bienert, G.P., M.D. Schüssler, and T.P. Jahn. (2008). Metalloids: essential, beneficial or toxic? Major intrinsic proteins sort it out. Trends Biochem. Sci. 33: 20-26.
Glycerol facilitator, GlpF. Transports various polyols with decreasing rates as size increases (Heller et al. 1980); also transports arsenite (As(III) and antimonite (Sb(III)) (Meng et al., 2004). Oligomerization may play a role in determining the rates of transport (Klein et al. 2019). AQP water permeability through GlpF can be regulated by lipid bilayer asymmetry and the transmembrane potential. The conserved Arg in the selectivity filter and positions and dynamics of multiple other pore lining residues modulate water passage through GlpF (Pluhackova et al. 2022).
GlpF of E. coli
Aqp1 of 270 aas and 6 TMSs. Induced by NH3 but not CO2, but transports both gases. Aqp1 is found in the plasma membrae as well as the ER/chloroplast. Aqp1 may be involved in photoprotection. It may facilitate the efflux of NH3, preventing the uncoupling effect of high intracellular ammonia concentrations (Matsui et al. 2018).
Aqp1 of Phaeodactylum tricornutum, a marine photoautotrophic diatoms
Tonoplast intrinsic protein, TIPA or Tip3.1, of 268 aas and 6 TMSs. Phylogenetic distribution, structure, transport dynamics, gating mechanism, sub-cellular localization, tissue-specific expression, and co-expression of TIPs have been reviewed to define their versatile role in plants (Sudhakaran et al. 2021). Based on the phylogenetic distribution, TIPs are classified into five distinct groups with aromatic-arginine (Ar/R) selectivity filters, typical pore-morphology, and tissue-specific gene expression patterns. The tissue-specific expression of TIPs is conserved among diverse plant species, especially for TIP3s, which are expressed exclusively in seeds. The solute specificities of TIPs plays a role in physiological processes like stomatal movement and vacuolar sequestration as well as in alleviating environmental stress. TIPs also play a role in growth and developmental processes like radicle protrusion, anther dehiscence, seed germination, cell elongation, and expansion. The gating mechanism of TIPs regulates the solute flow in response to external signals, which helps to maintain the physiological functions of the cell (Sudhakaran et al. 2021).
TIP of Arabidopsis thaliana (P26587)
Aquaporin TIP2-1 (Delta-tonoplast intrinsic protein) (Delta-TIP) (Tonoplast intrinsic protein 2-1) (AtTIP2;1) (Daniels et al. 1996). Transports water and ammonia, and can be activated by mercury (Kirscht et al. 2016). The 3-d structure is known to 1.2Å resolution (Kirscht et al. 2016). It may participate in vacuolar compartmentation and detoxification of ammonium.
TIP2-1 of Arabidopsis thaliana
Uncharacterized protein of 295 aas and 6 TMSs.
UP of Volvox carteri
The Aquaporin-8 (Aqp8) transporter is permeable to water, NH3, formamide and H2O2, and it is present in the inner membrane of mitochondria and the plasma membrane (Bienert et al., 2007; Saparov et al., 2007; Soria et al., 2010). Cholesterol, via sterol regulatory element-binding protein (SREBP) transcription factors, activates or represses genes involved in its hepatic biosynthetic pathway, and also modulates the expression of hepatocyte mitochondrial aquaporin-8 (mtAQP8), a channel that can function as peroxiporin by facilitating the transmembrane diffusion of H2O2. The peroxiporin, mtAQP8, plays a role in the SREBP-controlled hepatocyte cholesterogenesis (Danielli et al. 2019). Aquaporin-8 is important for cytokine-mediated toxicity in rat insulin-producing cells (Krüger et al. 2021). Aquaporin-8 ameliorates hepatic steatosis through the farnesoid X receptor in obese mice (Xiang et al. 2023).
Aqp8 of Homo sapiens (O94778)
Aqp8a.1 of 260 aas and 6 TMSs. The spaciotemporal pattern of induction of three aquaporins during embyonic development in Zebrafish has been determined, and all three, Aqp8a.1, Aqp8a.2 and Aqp8b, show distictive patterns (Koun et al. 2016).
Aqp8a.1 of Danio rerio (Zebrafish) (Brachydanio rerio)
Aquaporin of 250 aas and 6 TMSs. It is a water channel required to facilitate the transport of water across membranes; it is involved in osmotolerance (Ghosh et al. 2006).
Aquaporin of Encephalitozoon cuniculi (Microsporidian parasite)
Tonoplast intrinsic protein 1.1 of 251 aas and probably 6 TMSs. TIPs control water trade among cytosolic and vacuolar compartments and can also transport glycerol, ammonia, urea, hydrogen peroxide, metals/metalloids, and several amino acids (Liu et al. 2003). Additionally, TIPs, which can be responsive to nitrogen availability and salt sensitivity, are engaged with different abiotic stress responses and developmental processes like leaf expansion, root elongation and seed germination (Fan et al. 2023). TIPs of rice have also been studied (Balasaheb Karle et al. 2020).
Tip1.1 of Arabidopsis thaliana (P25818)
Endoplasmic reticulum Small and Basic Intrinsic Protein; (SIP1;1) water channel (present in all plant tissues except seeds) (Ishikawa et al., 2005) May play a role in gas and water exchange between the plant and its environment via stromata (turgor-driven epidermal valves) and the hydathode pore (Pillitteri et al., 2008).
SIP1;1 of Arabidopsis thaliana (Q9M8W5)
Tip1;3 of Arabidopsis thaliana (O82598)
The pollen-specific water/urea aquaporin. Tip5;1 (Soto et al. 2008) An aquaporin specifically targeted to pollen mitochondria; probably involved in nitrogen remobilization (Soto et al., 2010).
Tip5;1 of Arabidopsis thaliana (Q9STX9)
Aquaporin-B, AqpB of 294 aas and 6 TMSs. Tyr216 in loop D is a key residue in gating, possibly involving phosphorylation. Mutation of Tyr216 to aspartate or glutamate initiated water permeability. The truncated, permanently open AqpB yielded cells with reduced capability to cope with hypotonic stress (von Bülow et al. 2015).
AqpB of Dictyostelium discoideum
Plasma membrane aquaporin 1, PIP1, PIP1;2, PIP1b, of 286 aas and 6 TMSs (Törnroth-Horsefield et al., 2006). Transports H2O, H2O2 (Dynowski et al., 2008), O2 and CO2 (Zwiazek et al. 2017). Forms active heterotetramers with PIP2;1 (1.A.8.11.4); down regulated under drought stress (Najafabadi et al., 2008); plays a role in salt tolerance (Li et al. 2018). Gated by H+, Ca2+, Mn2+ and Cd2+ (Verdoucq et al., 2008). The wheat orthologue has been described (Ayadi et al., 2011). 96% identical to PIP1;3. In Selaginella moellendorffii (Sm; spikemoss), SmPIP1;1 is retained in the ER while SmPIP2;1 is found in the plasma membrane but, upon co-expression, both isoforms are found in the plasma membrane as a heterotetramer, leading to a synergistic effect on water membrane permeability (Bienert et al. 2018). In some speices, PIP1 is inactive (e.g., in maize), but formation of a hetrotetramer with PIP2 allows transport (Vajpai et al. 2018). Transmembrane helices 2 and 3 determine the localization of plasma membrane PIPs (Wang et al. 2019). PIP1;2 from Malus domestica confers salt tolerance in transgenic Arabidopsis (Wang et al. 2022).
PIP1.1 of Arabidopsis thaliana (P61837)
Plasma membrane intrinsic protein 2a (forms active heterotetramers with PIP1;1 (TC# 1.A.8.11.3); down regulated under drought stress (Najafabadi et al., 2008). Transports H2O2 (Dynowski et al., 2008). The Mesembryanthemum crystallinum PIP2;1 orthologue is an aquaporin impermeable to urea and glycerol. It is positively regulated by PKA- and PKC- mediated phosphorylation (Amezcua-Romero et al., 2010). PIP1;1 and PIP2;2 (Q9ATM8) co-expression modulates the membrane water permeability in the halophyte Beta vulgaris storage root through a pH regulatory response, enhancing membrane versatility to adjust its water transfer capacity (Bellati et al., 2010). The wheat orthologue has been described (Ayadi et al., 2011). Inter-TMS interactions occurring both within and between monomers play crucial roles in tetramer formation, and assembly of tetramers is critical for their trafficking from the ER to the plasma membrane as well as water permeability (Yoo et al. 2016). This protein as well as 1.A.8.11.6 is possibly orthologous to spinach PIP1;2 for which the crystal structure is available (PDP# 4JC6) (Berny et al. 2016). Plays a role in drought and salt tolerance (Wang et al. 2015). PIP-type aqauporins may also transport CO2, boric acid, glycerol, arsenic and Na+ (Byrt et al. 2017). TMS2 and TMS3 are necessary and sufficient in AtPIP2 for its PM localization (Wang et al. 2019).
PIP2;1 of Arabidopsis thaliana (P43286)
Probable aquaporin PIP2-6 (Plasma membrane intrinsic protein 2-6) (AtPIP2;6) (Plasma membrane intrinsic protein 2e) (PIP2e). In the radish (Raphaus sativus), there are 61 genes encoding aquaporins, and RsPIP2-6 is induced with high NaCl, and is involved in the salt stress response (Yi et al. 2022).
PIP2-6 of Arabidopsis thaliana
Aquaporin PIP2-8 (Plasma membrane intrinsic protein 2-8) (AtPIP2;8) (Plasma membrane intrinsic protein 3b) (PIP3b). This protein as well as 1.A.8.11.4 are possibly orthologous to spinach PIP1;2 for which the crystal structure is available (PDP# 4JC6) (Berny et al. 2016).
PIP2-8 of Arabidopsis thaliana
Aquaporin PIP2;5 (PIP2-5) of 285 aas. Transports water and hydrogen peroxide (H2O2) (Bienert et al. 2014). PIP1;2 doesn't transport H2O2. TMS3 contains an LxxA motif that targets the protein to the plasma membrane from the ER. While PIP2s are in the plasma mebrane, PIP1s are retained in the ER; this motif only partly explains the difference (Chevalier and Chaumont 2015). PIP1;2 AND PIP2;5 form homo- and heterotetramers (Berny et al. 2016). PIP2;6 is 85% identical, and Ytterbium, Yb3+, increases water flow in corn roots by activiating PIP2;6, PIP2;2 and TIP2;2 (Vorob'ev et al. 2019).
PIP2;5 of Zea mays
Aqp2 of 297 aas and 6 TMSs. Induced by both NH3 and CO2, and transports both gases. Aqp2 is found in the plasma membrane and may be involved in photoprotection. It may facilitate the efflux of NH3, preventing the uncoupling effect of high intracellular ammonia concentrations (Matsui et al. 2018).
Aqp2 of Phaeodactylum tricornutum, a marine photoautotrophic diatoms
Water channel, Aqp2-3 or Aqp2;3 or PIP2C of 285 aas and 6 TMSs. Ectopic expression of CrPIP2;3, a plasma membrane intrinsic protein gene from the halophyte, Canavalia rosea, enhanced drought and salt-alkali stress tolerance in Arabidopsis (Zheng et al. 2021). The Arabidopsis ortholog is presented here.
PIP2C of Arabidopsis thaliana
Nodulin-26 aquaporin and glycerol facilitator, NIP (de Paula Santos Martins et al. 2015). Transports NH3 5-fold better than water in Hg2+-sensitive fashion (Hwang et al., 2010).
Nodulin-26 of Glycine max (spP08995)
Uncharacterized MIP family protein of 274 aas and 6 TMSs.
UP of Entamoeba histolytica
Uncharacterized MIP family protein of 314 aas and 8 putative TMSs. The extra 2 non-homologous TMSs appear to be N-terminal.
UP of Entamoeba histolytica
Rice NIP2.1 (NIP2-1; NIP2;1) of 295 aas and 6 or 7 TMSs. It transports metaloids such as arsenous acid (arsenic) and silisic acid (silicon). The 3-D structure has been determined (Sharma et al. 2023). This protein is most similar to TC# 1.A.8.12.2 within TCDB.
NIP2.1 of Zea mays
The silicon (silicic acid) (undissociated form) transporter, Lsi1 (Ma et al., 2007a, b; Mitani et al., 2008). The barley orthologue Lsi1 (also called NIP2-1) is also a silicon (silicic acid) uptake channel (Chiba et al., 2009). Rice Lsi1 also transports arsenite and pentavalent mono and dimethyl arsenite (Li et al., 2009). In addition to silicon (Si), selenite (Se) uptake is mediated by Lsi1 (Zhao et al., 2010). Physicochemical and transcriptomic responses of Lactobacillus brevis JLD715 to sodium selenite have been reported (Yang et al. 2021). Many of the world's most important food crops such as rice, barley and maize accumulate silicon (Si) to high levels, resulting in better plant growth and crop yields (van den Berg et al. 2021). The first step in Si accumulation is the uptake of silicic acid by the roots, a process mediated by the NIP subfamily of aquaporins, also named metalloid porins. van den Berg et al. 2021 presented the X-ray crystal structure of the archetypal NIP family member from Oryza sativa (OsNIP2;1). The OsNIP2;1 channel is closed in the crystal structure by the cytoplasmic loop D, which is known to regulate channel opening in classical plant aquaporins. The structure reveals a novel, five-residue extracellular selectivity filter with a large diameter. Unbiased molecular dynamics simulations show a rapid opening of the channel to visualise how silicic acid interacts with the selectivity filter prior to transmembrane diffusion. These results may enable detailed structure-function studies of metalloid porins, including the basis of their substrate selectivity (van den Berg et al. 2021). Silicon (Si), the most abundant mineral element in the earth's crust, is taken up by plant roots in the form of silicic acid through Low silicon rice 1 (Lsi1). Lsi1 belongs to the Nodulin 26-like intrinsic protein subfamily and shows high selectivity for silicic acid. The crystal structure of rice Lsi1 at a resolution of 1.8 Å reveals transmembrane helical orientations different from other aquaporins, characterized by a unique, widely opened, and hydrophilic selectivity filter composed of five residues. Structural, functional, and theoretical investigations provided a solid basis for the Si uptake mechanism in plants (Saitoh et al. 2021).
Lsi1 of Oryza sativa (Q6Z2T3)
The boric acid channel protein, NIP5;1 (expressed in the root elongation zone and root hairs in response to boron deficiency) (Takano et al., 2006). Borate is an essential nutrient in plants. The ortholog in Brassica napus ( XP_013652160.1) is 301 aas in length with 6 TMSs and is 90% identical to the A. thaliana protein. Synthesis of the B. napus protein is induced in roots and shoots by a borate deficiency (Diehn et al. 2019). NIP2, 3, 4, 6 and 7 can also transport boric acid (Diehn et al. 2019). the grape ortholog can transport the same molecules (Sabir et al. 2020).
NIP5;1 of Arabidopsis thaliana (NP_192776)
The silicon (silicic acid) transporter, Nip2-2 (Nip2;2) (Mitani et al., 2008). Also transports arsenite (Li et al., 2009).
Nip2-2 of Oryza sativa (Q67WJ8)
Nip7;1 arsenite and borate channel (Isayenkov and Maathuis, 2008; Li et al., 2011)
Nip7. 1 of Arabidopsis thaliana (Q8LAI1)
Aquaporin NIP1-2 (NOD26-like intrinsic protein 1-2) (AtNIP1;2) (Nodulin-26-like major intrinsic protein 2) (NodLikeMip2) (Protein NLM2). Selectivity filters play roles in determining aluminum transport by AtNIP1;2 (Wang et al. 2021).
NIP1-2 of Arabidopsis thaliana
Aquaporin NIP1-1 (NOD26-like intrinsic protein 1-1) (AtNIP1;1) (Nodulin-26-like major intrinsic protein 1) (NodLikeMip1) (Protein NLM1). NIP-like aquaporins transport water, but also arsenic, boric acid, sliicon, glycerol, urea, lactic acid and ammonia (Mitani-Ueno et al. 2011; Hwang et al. 2010). The grape ortholog appears to transport the same molecules including water and glycerol, but also arsenate, borate, selenate and cadmium (Sabir et al. 2020).
NIP1-1 of Arabidopsis thaliana
Aquaporin NIP6-1 (NOD26-like intrinsic protein 6-1) (AtNIP6;1). The grape ortholog is impermeable to water, but permeable to glycerol (Sabir et al. 2020).
NIP6-1 of Arabidopsis thaliana
Hg2+-inhibitable aquaporin, AqpM (transports both water and glycerol as well as CO2) (Kozono et al., 2003; Araya-Secchi et al., 2011). Its 3-d structure has been determined to 1.7 Å. In AqpM, isoleucine replaces a key histidine residue found in the lumen of water channels, which becomes a glycine residue in aquaglyceroporins. As a result of this and other side-chain substituents in the walls of the channel, the channel is intermediate in size and exhibits differentially tuned electrostatics when compared with the other subfamilies (Lee et al. 2005).
AqpM of Methanothermobacter marburgensis
Putative aquaporin, GlpF5, of 216 aas; probably transports water, glycerol and dihydroxyacetone (Bienert et al. 2013).
GlpF5 of Lactobacillus plantarum
Aquaporin, Aqp, of 222 aas and 6 TMSs. It functions in hydrogen peroxide (H2O2) export from the cell, relieving oxidative stress (Tong et al. 2019). It is an H2O2-inducible bacterial "peroxiporin".
Aqp of Streptococcus oligofermentans or Streptococcus cristatus
Aquaporin, Aqp9, of 231 aas and 6 TMSs. This protein co-localizes with the vacuolar proton pyrophosphatase to acidocalcisomes and the contractile vacuole complex (Montalvetti et al. 2004) which are involved in osmoregulation (Rohloff et al. 2004). Acidocalcisomes function as storage sites for cations and phosphorus, participate in PPi and poly P metabolism as well as volume regulation and are essential for virulence. A signalling pathway involving cyclic AMP generation is important for fusion of acidocalcisomes to the contractile vacuole complex, transference of aquaporin and volume regulation (Docampo et al. 2011). Hyperosmotic stress induces aquaporin-dependent cell shrinkage, polyphosphate synthesis, amino acid accumulation, and global gene expression changes in Trypanosoma cruzi (Li et al. 2011). Plasmodium spp. express a single AQP, Toxoplasma gondii two, while Trypanosoma cruzi and Leishamnia spp. encode up to five AQPs. Their AQPs are thought to import metabolic precursors and simultaneously to dispose of waste and to help parasites survive osmotic stress (Von Bülow and Beitz 2015).
Aqp9 of Trypanosoma cruzi
Aquaporin of 214 aas and 6 TMSs in a 2 + 1 + 2 + 1 TMS arrangement.
Aqp of Bacteroidia bacterium (subsurface metagenome)
Putative aquaporin, Aqp2, with a large 300 residue amino terminal hydrophilic domain. The protein is of 603 aas and 7 TMSs in a 1 + 3 + 3 TMS arrangement.
Aqp2 of Plasmodium falciparum
Erythrocyte membrane-associated antigen, putative, of 541 aas and 4 - 7 TMSs.
EMA of Plasmodium yoelii yoelii
Erythrocyte membrane-associated antigen, putative, of 651 aas and 7 TMSs in a 1 + 3 + 3 TMS arrangement.
Aqp, putative, of Plasmodium yoelii yoelii
Aquaglyceroporin of 270 aas and 6 TMSs.
Aquaporin of Paramecium bursaria chlorella virus MT325
Lmo1539 of 272 aas and 7 possible TMSs. Lmo1539 is related to activation of the LiaR-mediated stress defense mechanism and is induced by treatment with nisin (TC# 1.C.20.1.1) (Pinilla et al. 2021).
Lmo1539 of Listeria monocytogenes
Aquaglyceroporin, AagP, of 298 aas and 6 TMSs. This protein transports water, glycerol and H2O2. It catalyzes H2O2 efflux during glycerol uptake and contributes to virulence in mice (Zhu et al. 2023).
AagP of Streptococcus suis
Mixed function glycerol facilitator/aquaporin, GlpF (Froger et al. 2001).
GlpF of Lactococcus lactis
GlpF of Mycoplasma gallisepticum )
GlpF1; transports water, dihydroxyacetone and glycerol as well as D,L-lactic acid (Bienert et al. 2013).
GlpF1 of Lactobacillus plantarum
GlpF2. Transporter of water, dihydroxyacetone and glycerol (Bienert et al. 2013).
GlpF2 of Lactobacillus plantarum
GlpF3. Transports water, dihydroxyacetone and glycerol (Bienert et al. 2013).
GlpF3 of Lactobacillus plantarum
GlpF4. Transports water, dihydroxyacetone and glycerol as well as D,L-lactic acid (Bienert et al. 2013).
GlpF4 of Lactobacillus plantarum
Putative aquaporin, GlpF6. Probably transports water, glycerol and dihydroxyacetone (Bienert et al. 2013).
GlpF6 of Lactobacillus plantarum
Glycerol facilitator, GlpF, of 248 aas and 6 TMSs
GlpF of Blattabacterium sp. subsp. Blattella germanica (strain Bge) (Blattella germanica symbiotic bacterium)
Aquaporin Z water channel (aqpZ gene expression is under sigma S control; induced at the onset of stationary phase) (Mallo and Ashby, 2006). The high resolution 3-d structure is available (PDB 1RC2) revealing two re-entrant coil-helix domains from the selectivity filter (Savage et al. 2003). Coupled mutations enabled glycerol transport (Ping et al. 2018).
AqpZ of E. coli (P60844)
Intracellular endoplasmic reticulum (ER)-localized Aquaporin 11 (Aqp11, AqpX1) water channel (important for the development of kidney proximal tubules; disruption produces neonatally fatal polycystic kidneys (Ishibashi 2006). Has a positively charged C-terminal amino acid cluster similar to the di-lysine motif (-KKXX) for ER retention (Nozaki et al., 2008)). In the horse, AQP3 and AQP11 are involved in the resilience of stallion sperm to withstand cryopreservation (Bonilla-Correal et al. 2017).
Aqp11 of Homo sapiens (Q8NBQ7)
Aquaporin-12A (AQP-12) of 295 aas and probably 7 TMSs with an extra N-terminal TMS. It bears a C-terminal KKXX-like ER retention sequence and is found intracelllularly (Ishibashi 2006). It is expressed in elevated amounts in exocrine glandular cells of the pancreas (Danielsson et al. 2014) but is also present in the nuclear envelope. A short perinuclear amphipathic α-helix in Apq12 promotes nuclear pore complex biogenesis (Zhang et al. 2021).
AQP12A of Homo sapiens
Aquaporin 10, Aqp10 of 259 aas and 6 TMSs
Aqp10 of Haemonchus contortus (Barber pole worm)
Aquaporin of 263 aas and 7 TMSs (Stavang et al. 2015).
Aquaporin of the salmon leach, Lepeophtheirus salmonis
Aquaporin of 256 aas with 6 TMSs in a 3 (N-terminus) + 3 TMS (C-terminus) arrangement (Zhou et al. 2018).
Aqp of Blomia tropicalis (mite)
Aquaporin of 261 aas and 6 TMSs. Aquaporins may not play major roles in adapting to longterm survival in brackish water or they be regulated by non-transcriptional mechanisms like post-translational modifications (Misyura et al. 2020).
Aqp of Aedes aegypti (Yellowfever mosquito) (Culex aegypti)
FPS1 glycerol efflux facilitator. It is important for maintaining osmotic balance during mating-induced yeast cell fusion and for tolerating hypoosmotic shock; it also transports arsenite and antimonite). FPS1 is a homotetramer (Beese-Sims et al., 2011). It is important for osmo-adaptation by regulating intracellular glycerol levels during changes in external osmolarity. Upon high osmolarity conditions, yeast accumulate glycerol by increased production of the osmolyte and by restricting glycerol efflux through Fps1. The extended cytosolic termini of Fps1 contain short domains that are important for regulating glycerol flux through the channel (Hedfalk et al. 2004). The transmembrane core of the protein plays an equally important role (Geijer et al., 2012). The MAP kinase, Slt2, physically interacts with Fps1, and this interaction, dependent on phosphorylation of S537, regulates arsenite uptake (Ahmadpour et al. 2016). The N-terminal regulatory domain and the B-loop may interact in channel control (Karlgren et al. 2004). Fps1 resides in multi tetrameric clusters, and hyperosmotic and oxidative stress conditions cause Fps1 reorganization, and rapid exposure to hydrogen peroxide causes Fps1 degradation (Shashkova et al. 2021). Activation of the CWI pathway through high hydrostatic pressure, enhances glycerol efflux via Fps1 in Saccharomyces cerevisiae (see family 9.B.454 in TCDB).
FPS1 protein of Saccharomyces cerevisiae
Fps1 hyperactive orthologue of the S. cerevisiae Fps1 (1.A.8.5.1) (Geijer et al., 2012).
Fps1 of Ashbya gossypii (Q75CI7)
Aquaporin, Aqy1 (PIP2-7 7). The subangstron (0.88Å) structure is available (Kosinska Eriksson et al. 2013). the H-bond donor interactions of the NPA motif''s asparagine residues to passing water molecules are revealed. A polarized water-water H-bond configuration is observed within the channel. Four selectivity filter water positions are too closely spaced to be simultaneously occupied. Strongly correlated movements break the connectivity of selectivity filter water molecules to other water molecules within the channel, thereby preventing proton transport via a Grotthuss mechanism.
Aqy1 of Komagataella pastoris (Pichia pastoris)
Water and CO2 permeable aquaporin, AQP1, of an edible mycorhizal fungus (desert truffles) (Navarro-Ródenas et al. 2012).
AQP1 of Terfezia claveryi
Tobacco X-intrinsic protein (XIP1-1-β). Transports glycerol, urea and boric acid, but not water (Bienert et al., 2011).
XIP1-1 of Nicotiana tomentosiformis (E3UN01)
Potato X intrinsic protein, XIP1. Transports glycerol, urea and boric acid, but not water (Bienert et al., 2011).
XIP1-1 of Solanum tuberosum (E3UMZ6)
Morning glory XIP-1-1-α. Transports glycerol, urea and boric acid, but not water (Bienert et al., 2011).
XIP1 of Ipomoea nil (E3UMZ5)
Aquaporin F (AqpF) of 321 aas and 6 TMSs. It transports water and glycerol, but additionally transporters hydrogen peroxide (H2O2) for signaling purposes (Laothanachareon et al. 2023). It may be the only aquaporin capable of H2O2 transport and signalling.
AqpF of Aspergillus niger
Aquaporin 1 (CO2-, O2-, H202- and nitrous oxide-permeable and water-selective) (Zwiazek et al. 2017; Varadaraj and Kumari 2020). Aquaporin-1 tunes pain perception by interacting with Na(v)1.8 Na+ channels in dorsal root ganglion neurons (Zhang and Verkman, 2010). It is upregulated in skeletal muscle in muscular dystrophy (Au et al. 2008). AQP1 has been reported to first insert as a four-helical intermediate, where helices 2 and 4 are not inserted into the membrane. In a second step this intermediate is folded into a six-helical topology. During this process, the orientation of the third helix is inverted, and it can shift out the membrane core (Virkki et al. 2014). Its synthesis is regluated by Kruppel-like factor 2 (KLF2; Q9Y5W3) which also interacts directly with Aqp1 (Fontijn et al. 2015). A nanoscale ion pump has been derived artificially from Aqp1 (Decker et al. 2017). Mammalian AQP1 channels, activated by cyclic GMP, can carry non-selective monovalent cation currents, selectively blocked by arylsulfonamide compounds AqB007 (IC50 170 muM) and AqB011 (IC50 14 muM). Loop D-domain amino acids activate the channel for ion coductance (Kourghi et al. 2018). Water flux through AQP1s is inhibited by 1 - 10 mμM acetozolaminde (Gao et al. 2006). Aqp1 transports reactive oxygen and nitrogen species (RONS) which may induce oxidative stress in the cell interior. These RONS include both hydrophilic (H2O2 and OH) and hydrophobic (NO2 and NO) RONS (Yusupov et al. 2019). The position of the Arg-195 side chain shows a number of interactions for loop C (Dingwell et al. 2019). AQP1 play vital roles in cellular homeostasis at rest and during endurance running exercises (Rivera and Fahey 2019). AQP1 and AQP4 activities correlate with the severity of hydrocephalus induced by subarachnoid haemorrhage (Long et al. 2019). AQPs are related to osmoregulation and play a critical role in maturation, cryo-stability and motility activation in boar spermatozoa (Delgado-Bermúdez et al. 2019). In foetal kidney, AQP1 expression appeared in the apical and basolateral parts of cells, lining the proximal convoluted tubules and the descending limb of Henle's loop, then in the tubule pole of Bowman's capsule (Ráduly et al. 2019). Inhibition of aquaporin-1 prevents myocardial remodeling by blocking the transmembrane transport of hydrogen peroxide (Montiel et al. 2020). AQP1 Is up-regulated by hypoxia and leads to increased cell water permeability, motility, and migration in neuroblastoma (Huo et al. 2021). Aqp1 allows the transport of CO2 across membranes (Michenkova et al. 2021). Down-regulation of aquaporin-1 mediates a microglial phenotype switch affecting glioma growth (Hu et al. 2020). AQP1 expression is down-regulated following repeated exposure of UVB via MEK/ERK activation pathways, and this AQP1 reduction leads to changes of physiological functions in dermal fibroblasts (Kim et al. 2020). AQP1 and AQP7 are differentially regulated under hyperosmotic stress conditions, and AQP1 acts as an osmotic stress sensor and response factor (Aggeli et al. 2021).
Aquaporin 1 (AQP1) of Homo sapiens
Water and urea transporting aquaporin (cockroach) (Herraiz et al., 2011).
Aquaporin of Blatella germanica (G8YY04)
Water channel, Aqp1; inhibited by HgCl2 and tetraethylammonium. Plays a role in water homeostasis during blood feeding and humidity adaptation of A. gambiae, a major mosquito vector of human malaria in Africa (Liu et al., 2011).
Aqp1 of Anopheles gambiae (F2YNF6)
Aquaporin, Aqp1 in the gall fly. Transports water but not glycerol or urea. Promotes freeze-tolerance (Philip et al., 2011).
Aqp1 of Eurosta solidaginis (E4W5Y5)
The Drosophila melanogaster integral protein, DRIP (Ishida et al., 2012).
Aqp, DRIP of Drosophila melanogaster (Q9V5Z7)
MIP26 of Rana pipiens
Mercury-sensitive whitefly aquaporin-1 of the specialized filter chamber of the alimentary tract (Mathew et al. 2011).
Aquaporin-1 of Bemisia tabaci
Aquaporin-1 or Aquaporin1, Aqp1, of 258 aas and 6 TMSs. Three Aqp1 isoforms are differentially regluated by the function of the vasotocin (AVTR) and isotocin (ITR) receptors (Martos-Sitcha et al. 2015). Aqp1aa, one of two isoforms in teleosts, may play a role in spermatogenesis in Cynoglossus semilaevis (Guo et al. 2017).
Aqp1 of Sparus aurata (Gilthead sea bream)
Aquaporin-3, Aqp-3 of 271 aas. Transports water, glycerol, hydrogen peroxide and urea (Geadkaew et al. 2015). AQP3 induces the production of chemokines such as CCL24 and CCL22 through regulating the amount of cellular H2O2 in M2 polarized alveolar macrophages, implying a role of AQP3 in asthma (Ikezoe et al. 2016).
Aqp3 of Opisthorchis viverrini (liver fluke)
Aqp-x2 water channel in the luminal epithelium of urinary bladder cells and lungs. Responsive to Vasotocin (AVT) (Shibata et al. 2015).
Aqp-x2 of Xenopus laevis
Contractile vacuole aquaporin of 295 aas and 6 TMSs, Aqp. Shown to transport water, accounting for the high water permeability of the contractile vacuole (Nishihara et al. 2008).
Aqp of Amoeba proteus (Amoeba) (Chaos diffluens)
The lens fiber MIP aquaporin (Aqp0) of B. taurus (forms membrane junctions in vivo and double layered crystals in vitro that resemble the in vivo junctions). The water pore is closed in the in vitro structure (Gonen et al., 2004b). It interacts directly with the intracellular loop of connexin 45.6 via its C-terminal extension (Yu et al., 2005). Forms human cataract lens membranes (Buzhynskyy et al., 2007; Yang et al., 2011). A mutation that causes congenital dominant lens cataracts has been identified (Varadaraj et al. 2008). AqpO catalyzes Zn2+-modulated water permeability as a cooperative tetramer (Nemeth-Cahalan et al., 2007). It transports ascorbic acid (Nakazawa et al., 2011). The Detergent organization around solubilized aquaporin-0 using Small Angle X-ray Scattering has been reported (Berthaud et al., 2012). Aquaporin 0 (AQP0) in the eye lens is truncated by proteolytic cleavage during lens maturation. This truncated AQP0 is no longer a water channel (Berthaud et al. 2015). A mutation that causes congenital dominant lens cataracts has been identified (Varadaraj et al. 2008). Cataractogenesis in MIP mutants are probably caused by defects in MIP gene expression in mice (Takahashi et al. 2017). This may be caused by the ability of Aqp0 (as well as Aqp1 and Aqp5) to transport hydrogen peroxide (H2O2) which can cause cataracts (Varadaraj and Kumari 2020). An automated data processing and analysis pipeline for transmembrane proteins including Aqp0 in detergent solutions has been presented (Molodenskiy et al. 2020). EphA2 is required for normal Cx50 localization to the cell membrane, and conductance of lens fiber cells requires normal Eph-ephrin signaling and water channel (Aqp0) localization (Cheng et al. 2021). The local curvature of cellular membranes acts as a driving force for the targeting of membrane-associated proteins to specific membrane domains, as well as a sorting mechanism for transmembrane proteins, as demonstrated for Aqp0; AQP0 causes small negative curvature (Kluge et al. 2022).
Major intrinsic protein (MIP or Aqp0) of Bos taurus
Aquaporin x5 of 273 aas and 6 TMSs, Aqp-x5. The sequence reveals a mercurial-sensitive cysteine and a putative phosphorylation motif site for protein kinase A at Ser-257 (Kubota et al. 2006). A swelling assay using Xenopus oocytes revealed that AQP-x5 facilitated water permeability. Expression of AQP-x5 mRNA was restricted to the skin, brain, lungs and testes. Immunofluorescence and immunoelectron microscopical studies using an anti-peptide antibody (ST-156) against the C-terminal region of the AQP-x5 protein revealed the presence of immunopositive cells in the skin, with the label predominately localized in the apical plasma membrane of the secretory cells of the small granular glands. These glands are unique both in being close to the epidermal layer of the skin and in containing mitochondria-rich cells with vacuolar H+-ATPase dispersed among its secretory cells. Results from immunohistochemical experiments on the mucous or seromucous glands of several other anurans verified this result (Kubota et al. 2006).
Aqp-x5 of Xenopus laevis (African clawed frog)
Aqp-1A of 258 aas and 6 TMSs, DRIP1. Transports water but not glycerol or urea. Functions in water homeostasis in many tissues and stages of development (Lu et al. 2018). An aquaporin in the beet armyworm, Spodoptera exigua, (79% identical to the one in Chilo suppressalis, mediates cell shape change required for cellular immunity (Ahmed and Kim 2019).
Aqp-1A of Chilo suppressalis (Asiatic rice borer moth)
Aqp-2A of 269 aas and 6 TMSs, PRIP2. It transports water and urea but not glycerol or trehalose. It functions in water homeostasis in many tissues and stages of development (Lu et al. 2018). Its production in various tissues and stages of growth have been examined (Lu et al. 2021).
Aqp-2A of Chilo suppressalis (Asiatic rice borer moth)
Big brain-like protein of 309 aas and 6 probable TMSs, BibL1 (Lind et al. 2017).
BibL1 of the euryhaline bay barnacle, Balanus improvisus (Darwin, 1854) (Amphibalanus improvisus)
Aquaporin 1, AQP1, of 261 aas and 6 TMSs, which selectively transports water (Lind et al. 2017).
AQP1 of the euryhaline bay barnacle Balanus improvisus (Darwin, 1854) (Amphibalanus improvisus)
Aquaporin (Aqp) of 458 aas, 6 N-terminal TMSs and a 200 aa hydrophilic C-terminal domain.
Aqp of Blomia tropicalis (mite)
Aquaglyceroporin, Glp1, of 269 aas and 6 TMSs. Transports glycerol and water (Tsujimoto et al. 2017).
Glp1 of Cimex lectularius (Bed bug) (Acanthia lectularia)
Aquaporin-2, Aqp2, of 275 aas and 6 TMSs.It is subject to hyperosmotic stimulation in Chick Kidney (Sugiura et al. 2008). It is highly similar to the quail (Coturnix coturnix) ortholog which has been studied and shown to be a mercury-inhibited, vasotocin-sensitive water channel in the kidney (Yang et al. 2004).
Aqp2 of Gallus gallus
Aquaporin/glycerol transporter of 294 aas and 6 TMSs. Tandem duplication (TD) was the major mechanism of gene expansion in echinoderms and hemichordates, which, together with whole genome duplications (WGD) in the chordate lineage, continued to shape the genomic repertoires in craniates. Molecular phylogenies indicated that Aqp3-like and Aqp13-like channels were the probable stem subfamilies in craniates, with WGD generating Aqp9 and Aqp10 in gnathostomes but Aqp7 arising through TD in Osteichthyes (Yilmaz et al. 2020).
Aqp of Saccoglossus kowalevskii (Acorn worm)
The Big Brain, BIB aquaporin of 696 aas and 6 TMSs, transports ions by a channel mechanism involving E71 in TMS1) (Yool, 2007). BIB expressed in Xenopus oocytes is a monovalent cation channel modulated by tyrosine kinase signaling. BIB conductance shows voltage- and dose-dependent block by extracellular divalent cations Ca2+ and Ba2+ but not by Mg2+ in wild-type channels (Yanochko and Yool 2004). Site-directed mutagenesis of negatively charged glutamate (Glu274) and aspartate (Asp253) residues had no effect on divalent cation block, but mutation of Glu71 in the first TMS altered channel properties (Yanochko and Yool 2004).
Big brain (BIB) of Drosophila melanogaster
Aquaporin-A, AqpA of 249 aas and 6 TMSs. Aquaporins may not play major roles in adapting to longterm survival in brackish water or they be regulated by non-transcriptional mechanisms like post-translational modifications (Misyura et al. 2020).
AqpA of Aedes aegypti (Yellowfever mosquito) (Culex aegypti)
Aqp1 of 250 aas and 6 TMSs. Aqp1 localizes on the contractile vacuole complex in Paramecium multimicronucleatum (Ishida et al. 2021).
Aqp1 of Paramecium multimicronucleatum
Major intrinsic protein superfamily, aquaporin-like protein. MIP2, of 247 aas and 6 TMSs.
MIP2 of Chlamydomonas reinhardtii (Chlamydomonas smithii)
Aqp6 aquaporin (also transports NO3- and other anions at acidic pH or in the presence of Hg2+) (Ikeda et al., 2002). AQP6 flicker rapidly between closed and open states. Two well conserved glycine residues: Gly-57 in TMS 2 and Gly-173 in TMS 5 reside at the contact point where the two helices cross. Mammalian orthologs of AQP6 have an asparagine residue (Asn-60) at the position corresponding to Gly-57 in Aqp6. Liu et al. 2005 showed that a single residue substitution (N60G in rat AQP6) eliminates anion permeability but increases water permeability.
Aqp6 of Homo sapiens
Aquaporin-4 (AQP4) is the major water channel in the central nervous system and plays an important role in the brain's water balance, including edema formation and clearance. There are 6 splice variants; the shorter ones assemble into functional, tetrameric square arrays; the longer is palmitoylated on N-terminal cysteyl residues) (Suzuki et al., 2008). The longest, Aqp4e, has a novel N-terminal domain and forms a water channel in the plasma membrane although various shorter variants don't (Moe et al., 2008). AQP4, like AQP0 (1.A.8.8.2), forms water channels but also forms adhesive junctions (Engel et al., 2008) (causes cytotoxic brain swelling in mice (Yang et al., 2008)) Mice lacking Aqp4 have impaired olfactions (Lu et al., 2008). Aqp4 is down regulated in skeletal muscle in muscular dystrophy (Au et al. 2008). The crystal structure is known to 2.8 Å resolution (Tani et al., 2009). The structure reveals 8 water molecules in each of the four channels, supporting a hydrogen-bond isolation mechanism and explains its fast and selective water conduction and proton exclusion (Tani et al., 2009; Cui and Bastien, 2011). It is an important antigen in Neuromyelitis optica (NMO) patients (Kalluri et al., 2011). A connection has been made between AQP4-mediated fluid accumulation and post traumatic syringomyelia (Hemley et al. 2013). AQP4 has increased water permeability at low pH, and His95 is the pH-dependent gate (Kaptan et al. 2015). Also transports NH3 but not NH4+ (Assentoft et al. 2016). Cerebellar damage following status epilepticus involves down regulation of AQP4 expression (Tang et al. 2017). SUR1-TRPM4 and AQP4 form a complex to increase bulk water influx during astrocyte swelling (Stokum et al. 2017). A mutation, S111T, causes intellectual disability, hearing loss, and progressive gait dysfunction (Berland et al. 2018). As in humans, the chicken ortholog, Aqp4, is found in brain > kidney > stomach (Ramírez-Lorca et al. 2006). A Molecular Dynamics Investigation on Human AQP4 has been published (Marracino et al. 2018). AQP1 and AQP4 activities correlate with the severity of hydrocephalus induced by subarachnoid haemorrhage (Long et al. 2019). Di-lysine motif-like sequences formed by deleting the C-terminal domain of aquaporin-4 prevent its trafficking to the plasma membrane (Chau et al. 2021). Kidins220 deficiency causes ventriculomegaly via SNX27-retromer-dependent AQP4 degradation (Del Puerto et al. 2021). AQP4 expression is upregulated in cells exposed to dexamethasone, and SUMOylation [Small ubiquitin-like modifiers (SUMOs)] may participate in this regulation (Zhang et al. 2020). Simultaneous calmodulin binding to the N- and C-terminal cytoplasmic domains of aquaporin 4 has been demonstrated (Ishida et al. 2021). Aqp-4 plays a role in secondary pathological processes (spinal cord edema, glial scar formation, and inflammatory response) after spinal cord injury, SCI. Loss of AQP-4 is associated with reduced spinal edema and improved prognosis after SCI in mice, and downregulation of AQP-4 reduces glial scar formation and the inflammatory response after SCI (Pan et al. 2022). AQP4 contributes to the migration and proliferation of gliomas, and to their resistance to therapy. In glioma cell cultures, in both subcutaneous and orthotopic gliomas in rats, and in glioma tumours in patients, that transmembrane water-efflux rate is a sensitive biomarker of AQP4 expression (Jia et al. 2022). Aquaporin 4 is required for T cell receptor-mediated lymphocyte activation (Nicosia et al. 2023). Peripheral lung infections influence the blood brain barrier (BBB) water exchange, which appears to be mediated by endothelial dysfunction and is associated with an increase in perivascular AQP4 (Ohene et al. 2023). Trifluoperazine reduces apoptosis and inflammatory responses in traumatic brain injury by preventing the accumulation of Aquaporin4 on the surface of brain cells (Xing et al. 2023). Cation flux through SUR1-TRPM4 and NCX1 in astrocyte endfeet induces water influx through AQP4 and brain swelling after ischemic stroke (Stokum et al. 2023). Aquaporin-4 expression and modulation may be important in a rat model of post-traumatic syringomyelia (Berliner et al. 2023). The Aqp4 water channel may be a drug target for Alzheimer's Disease (Silverglate et al. 2023). A series of 2,4,5-trisubstituted oxazoles 3a-j were synthesized by a Lewis acid mediated reaction of aroylmethylidene malonates with nitriles. In silico studies conducted using the protein data bank (PDB) structure 3gd8 for AQP4 revealed that compound 3a would serve as a suitable candidate to inhibit AQP4 in human lung cells (NCI-H460). In vitro studies demonstrated that compound 3a could effectively inhibit AQP4 and inflammatory cytokines in lung cells, and hence it may be considered as a viable drug candidate for the treatment of various lung diseases (Meenakshi et al. 2023).
AQP4 of Homo sapiens (P55087)
Aqp1 of Polypedilum vanderplanki
Aqp2 water channel of the sleeping chironomid (functions in water homeostasis during anhydrobiosis (Kikawada et al., 2008).
Aqp2 of Polypedilum vanderplanki (A5A7P0)
Vasopressin-sensitive aquaporin-2 (Aqp2) in the apical membrane of the renal collecting duct (Fenton et al., 2008). Controls cell volume and thereby influences cell proliferation (Di Giusto et al. 2012). It plays a key role in concentrating urine. Water reabsorption is regulated by AQP2 trafficking between intracellular storage vesicles and the apical membrane. This process is tightly controlled by the pituitary hormone arginine vasopressin, and defective trafficking results in nephrogenic diabetes insipidus (NDI). The crystal structure of Aqp2 has been solved to 2.75 Å (Frick et al. 2014). In terrestrial vertebrates, AQP2 function is generally regulated by arginine-vasopressin to accomplish key functions in osmoregulation such as the maintenance of body water homeostasis by a cyclic AMP-independent mechanism (Olesen and Fenton 2017; Martos-Sitcha et al. 2015). AQP2 is expressed in the anterior vaginal wall and fibroblasts, and regulates the expression level of collagen I/III i, suggesting that AQP2 is associated with the pathogenesis of stress urinary incontinence through collagen metabolism during ECM remodeling (Zhang et al. 2017). As in humans, the chicken ortholog, Aqp2, is found only in the kidney (Ramírez-Lorca et al. 2006). AQP2 is critical in regulating urine concentrating ability. The expression and function of AQP2 are regulated by a series of transcriptional factors and post-transcriptional phosphorylation, ubiquitination, and glycosylation (He and Yang 2019). Mutation or functional deficiency of AQP2 leads to severe nephrogenic diabetes insipidus, and inhibition of various aquaporins leads to many water-related diseases such as, edema, cardiac arrest, and stroke. Maroli et al. 2019 reported on the molecular mechanisms of mycotoxin (citrinin, ochratoxin-A, and T-2 mycotoxin) inhibition of AQP2 and arginine vasopressin receptor 2 (AVPR2). Aquaporin-2 mutations cause Nephrogenic diabetes insipidus (Li et al. 2021). Meniere's disease is affected by dexamethasone which is a direct modulator of AQP2. The molecular mechanisms involved in dexamethasone binding to and its regulatory action upon AQP2 function have been described (Mom et al. 2022). Interaction of cortisol with aquaporin-2 modulates its water permeability (Mom et al. 2023).
Aqp2 of Homo sapiens (P41181)
Aquaporin 5 (x-ray structure at 2.0 Å resolution (PDB# 3D9S) is available) (Horsefield et al., 2008). Aqp5 is a marker for proliferation and migration of human breast cancer cells (Jung et al., 2011). Plays a role in chronic obstructive pulmonary diseases (COPD) (Zhao et al. 2014). Its expression is regulated by androgens (Pust et al. 2015). As in humans, the chicken ortholog, Aqp5, is found in the intestine, the jejunum, ileum and colon (Ramírez-Lorca et al. 2006). Proteomic analyses of the ocular lens revealed palmitoylation (Wang and Schey 2018). Aquaporin 5 expression correlates with tumor multiplicity and vascular invasion in hepatocellular carcinoma (Vireak et al. 2019). The ability of Aqp5 (as well as Aqp0 and Aqp1) to transport hydrogen peroxide (H2O2) may cause cataracts in the eye (Varadaraj and Kumari 2020). AQP3 and AQP5 play important but different roles in spermatogenesis and sperm maturation in dogs (Mirabella et al. 2021). The up-regulation of AQP1, AQP3 and AQP5 in skin during summer season indicates roles in thermoregulation (Debbarma et al. 2020). Aqp5 interacts with TRPV4 (see 1.A.4.2.5 for the rat ortholog) (Kemény and Ducza 2022). AQP5 facilitates osmotically driven water flux across biological membranes as well as the movement of hydrogen peroxide and CO2. Various mechanisms dynamically regulate AQP5 expression, trafficking, and function. Besides fulfilling its primary water permeability function, AQP5 regulates downstream effectors (D'Agostino et al. 2023). Modulation of membrane trafficking of AQP5 in the lens in response to changes in zonular tension is mediated by TRPV1 (Petrova et al. 2023).
Aquaporin 5 of Homo sapiens (P55064)
Aquaporin 3. 95% identical to the human orthologue. Poorly permeable to water, but more permeable to glycerol and arsenic trioxide (Palmgren et al. 2017). It is expressed in the plasma membrane of basal epidermal cells in the skin; loss of function prevents skin tumorigenesis and epidermal cell proliferation (Hara-Chikuma and Verkman, 2008). The human orthologue also transports both water and glycerol and is the predominant AQP in skin (Jungersted et al. 2013). It's function is necessary for normal proliferation of colon cancer cells due to glycerol uptake (Li et al. 2016). Aqp3 is implicated in cancer progression to the metastatic state as its function promotes cell migration and cell shape plasticity. Its synthesis is regulated by the AhR (aryl hydrocarbon (pollutant) receptor or dioxin receptor), a transcription factor triggered by environmental pollutants (Bui et al. 2016). Trefoil factor (TFF) peptides increase cell water permeability and induce prodcution of Aqp3 (Marchbank and Playford 2018). Although AQP3 and other similar transmembrane proteins do not themselves transport drugs, changes in their expression levels can cause changes in cell membrane fluidity, thus affecting drug absorption rates (Ikarashi et al. 2019). AQP3 levels are elevated in human endometrioid carcinoma (Watanabe et al. 2020). AQP3 and AQP5 play important roles in spermatogenesis and sperm maturation in dogs (Mirabella et al. 2021). AQP-1, 3 and 8 levels in amniotic fluid were measured in patients suffering from polyhydramnios. They were compared to the levels observed in control subjects, and their relationship with maternal factors and neonatal issues was analyzed. AQP-1, 3, 8 levels physiologically fluctuated, AQP-1 levels were the lowest and AQP-3 the highest, with a decrease at the end of pregnancy (Guibourdenche et al. 2021). The human ortholog, Aqp3 (Q92482) is 95% identical. It transports water, glycerol and urea, and is the blood group antigen, GIL (Roudier et al. 2002). Intra-endolymphatic sac steroids have regulatory effects on inner ear AQP-3 expression via the vestibular aqueduct and modulate the homeostasis of endolymphatic fluids (Kitahara et al. 2003).
Aquaporin 3 of Rattus norvegicus (P47862)
Aqp9 or Aqp-h9 of 294 aas. Takes up glycerol as well as water, and thereby contributes to freeze tolerance (Hirota et al. 2015). An almost identical orthologue, HC-9 in Dryophytes chrysoscelis (gray treefrog), similarly facilitates glycerol permeability. Both the transcriptional and translational levels of HC-9 change in response to thermal challenges, with a unique increase in liver during freezing and thawing (Stogsdill et al. 2017).
Aqp9 of Hyla japonica
Aqp1 of 304 aas and 6 TMSs; the most abundant transmembrane protein in the tegument of Schistosoma mansoni. This protein is expressed in all developmental stages and seems to be essential in parasite survival since it plays a crucial role in osmoregulation, nutrient transport and drug uptake (Figueiredo et al. 2014).
Aqp1 of Schistosoma mansoni (Blood fluke)
Basolateral Aqp3 of 292 aas and 6 TMSs in the frog urinary bladder (Shibata et al. 2015).
Aqp3 of Xenopus laevis
Aquaglycerolporin, Aqp (high permeability to ammonium, methylamine, glycerol and water) (Beitz et al., 2004) NH4+/NH3+CH3/glycerol/water transporter (Zeuthen et al., 2006).
Aqp of Plasmodium falciparum (CAC88373)
Glycerolaquaporin 9, Aqp9 of 295 aas and 6 TMSs. Transports water, glycerol and arsenic trioxide, As2O3 (Palmgren et al. 2017) as well as urea and lactic acid (but not lactate) (Geistlinger et al. 2022). Primary APL cells express AQP9 significantly (2-3 logs) higher than other acute myeloid leukemia cells (AMLs), explaining their exquisite As2O3 sensitivity (Leung et al. 2007). AQP-7 and AQP-9-mediated glycerol transport in tanycyte cells may be under hormonal control to use glycerol as an energy source during the mouse estrus cycle (Yaba et al. 2017). It transports multiple neutral and ionic arsenic species including arsenic trioxide, monomethylarsenous acid (MAs(III)) and dimethylarsenic acid (DMA(V)). It also transports clinically relevant selenium species including monomethylselenic acid (MSeA), especially at acidic pH. FCCP, valinomycin and nigericin do not significantly inhibit MSeA uptake, but AQP9 also transport ionic selenite and lactate, with low efficiency compared with MSeA uptake. Selenite and lactate uptake is pH dependent and inhibited by FCCP and nigericin but not valinomycin. The selenite and lactate uptake via AQP9 can be inhibited by different lactate analogs. AQP9 transport of MSeA, selenite and lactate is inhibited by an AQP9 inhibitor, phloretin, and the AQP9 substrate, arsenite (As(III)) (Geng et al. 2017). The host aquaporin-9 is required for efficient Plasmodium falciparum sporozoite entry into human hepatocytes (Amanzougaghene et al. 2021). RG100204 is a direct blocker of the AQP9 channel (Florio et al. 2022).
Aqp9 of Homo sapiens
Aquaporin 9, Aqp9, small solute channel 1 of 296 aas and 6 TMSs (Wang and Ye 2016).
Aqp9 of Echinococcus granulosus (Hydatid tapeworm)
Water/glycerol aquaglyceroporin 2, AQP2, of 294 aas and 6 TMSs (Lind et al. 2017).
AQP2 of the euryhaline bay barnacle, Balanus improvisus (Darwin, 1854) (Amphibalanus improvisus)
Glycerol-aquaporin of 332 aas and 6 TMSs (Stavang et al. 2015).
Aqp of the salmon leach, Lepeophtheirus salmonis
Aquaporin of 341 aas and 7 TMSs (Ben Amira et al. 2018).
Aqp of Hypocrea atroviridis (Trichoderma atroviride)
AQP2 (AQP9) of 312 aas and 6 TMSs; transports water, glycerol and urea as well as the drugs, melarsoprol and pentamidine (Schmidt et al. 2018). CCCP and gramicidin but not nigericin inhibit Trypanosoma brucei Aquaglyceroporins Aqp2 and Aqp3 at neutral pH (Petersen and Beitz 2020).
AQP2 of Trypanosoma brucei
Aquaporin-9 (Aqp9) (permeable to glycerol, urea, polyols, carbamides, purines, pyrmidines, nucleosides, monocarboxylates, pentavalent methylated arsenicals and the arsenic chemotherapeutic drug, trisenox (McDermott et al., 2009). It is poorly permeable to water and not permeable to β-hydroxybutyrate (Carbrey et al., 2003). (Regulated by CFTR and NHERF1 in response to cyclic AMP (Pietrement et al., 2008)) The 7 Å projection structure and a homology model revealed that pore-lining residues and the hydrophobic edge of the tripathic pore of GlpF (1.A.8.1.1) provide the basis for broad substrate specificity (Viadiu et al., 2007). It is important for urea transport in mouse hepatocytes (Jelen et al. 2012). Activation of the PPARα transcription factor results in reduction in the abundance of AQP9 in periportal hepatocytes, but its activation in the fed state directs glycerol into glycerolipid synthesis rather than into de novo synthesis of glucose (Lebeck et al. 2015). Azacytidine up-regulates AQP9 and enhances arsenic trioxide (As2O3)-mediated cytotoxicity in acute myeloid leukemia (AML) (Chau et al. 2015). Human Aqp9 transports hydrogen peroxide (HOOH) (Watanabe et al. 2016) and plays a role in certain types of cancer (Zheng et al. 2020). Human aquaporin 9 regulates Leydig cell steroidogenesis in diabetes (Kannan et al. 2022).
Aqp9 of Rattus norvegicus (P56627)
Aquaporin of 274 aas and 6 TMSs. See Zhou et al. 2018 for its identification.
Aqp of Blomia tropicalis (mite)
Aquaporin 3, Aqp3, of 304 aas and 6 TMSs. CCCP and gramicidin but not nigericin inhibit Trypanosoma brucei Aquaglyceroporins Aqp2 and Aqp3 at neutral pH (Petersen and Beitz 2020).
Aqp3 of Trypanosoma brucei
Aquaporin-3-like protein, Aqp10b, of 374 aas and 6 TMSs (Santos et al. 2004).
Aqp10b of Sparus aurata (gilthead seabream)
Aqp3 of 294 aas and 6 TMSs (Mashini et al. 2022).
Aqp3 of Exaiptasia diaphana
Aqp3 of 292 aas and 6 TMSs. It is a water channel required to promote glycerol permeability and water transport across cell membranes (Roudier et al. 2002, Gotfryd et al. 2018). It acts as a glycerol transporter in skin and plays an important role in regulating the stratum corneum and epidermal glycerol content. It is involved in skin hydration, wound healing, and tumorigenesis, and it provides the kidney medullary collecting duct with high permeability to water, thereby permitting water to move in the direction of an osmotic gradient. It is slightly permeable to urea and H2O2, and may function as a water and urea exit mechanism in antidiuresis in collecting duct cells. It may play an important role in gastrointestinal tract water transport and in glycerol metabolism. Breast cancer cell invasion and metastasis are related to AQP3, which is the transmembrane transport channel for H2O2 molecules (Zhong et al. 2022). AQP3 plays a key role in cancer and metastasis. RoT inhibits human AQP3 activity with an IC50 in the micromolar range (22.8 ± 5.8 µM for water and 6.7 ± 3.0 µM for glycerol permeability inhibition). RoT blocks AQP3-glycerol permeation by establishing strong and stable interactions at the extracellular region of AQP3 pores (Paccetti-Alves et al. 2023). AQP3-mediated activation of the AMPK/SIRT1 signaling pathway curtails gallstone formation in mice by inhibiting inflammatory injury of gallbladder mucosal epithelial cells (Wang et al. 2023).
Aqp3 of Homo sapiens
Major aquaglyceroporin, LmAQP1: transports water, glycerol, methylglyoxal, trivalent metalloids such as arsenite and antimonite, dihydroxyacetone and sugar alcohols. Also takes up the activated form or the drug, pentostam. It localizes to the flagellum of the Leishmania promastigotes and is used to regulate volume in response to hypoosmotic stress; it functions in osmotaxis (Figarella et al., 2005; Gourbal et al, 2004). The first line treatment for cutaneous leishmaniasis is pentavalent antimony such as sodium stibogluconate (pentostam) and meglumine antimonite (glucantime), and both compounds are transported by LmAQP1 (Eslami et al. 2020). The mutation G133D in the Leishmania guyanensis AQP1 is highly destabilizing (Tunes et al. 2021).
Aqp1 of Leishmania major (Q6Q1Q6)
Aquaporin 1 (permeable to water, glycerol, dihydroxyacetone and urea) (Uzcategui et al., 2004)
Aqp1 of Trypanosoma brucei (Q6ZXT4)
Aquaporin 10 of 301 aas and 6 TMSs. Cell- and tissue-specific expression of AQP-0, AQP-3, and AQP-10 in the testis, efferent ducts, and epididymis has been demonstrated (Hermo et al. 2019). It is also present in keratinocytes and the stratum corneum (Jungersted et al. 2013).
Aqp10 of Homo sapiens
Glycerol/water/urea/arsenic trioxide-transporting channel protein, aqaporin 7 or Aqp7, but water is a poor substrate (Palmgren et al. 2017). Present in adipose tissue where it allows glycerol efflux. Defects result in increased accumulation of triglycerides, obesity and adult onset (type 2) diabetes (Lebeck 2014). It may be a drug target for anti-type 2 diabetes (Méndez-Giménez et al. 2018). AQP-7- and AQP-9-mediated glycerol transport in tanycyte cells may be under hormonal control to use glycerol as an energy source during the mouse estrus cycle (Yaba et al. 2017). It may also influence whole body energy metabolism (Iena and Lebeck 2018) including in the kidney (Schlosser et al. 2023). Aquaporin-7-mediated glycerol permeability is linked to human sperm motility in asthenozoospermia and during sperm capacitation (Ribeiro et al. 2023).
Aqp7 of Homo sapiens
Glycerol uptake facilitator of 393 aas
Glycerol transporter of Cordyceps militaris (Caterpillar fungus)
Aquaporin/glycerol facilitator of 294 aas and 6 TMSs. May play a role in freeze tolerance (Hirota et al. 2015).
Aqp-9 of Xenopus tropicalis