9.A.14 The G-protein-coupled receptor (GPCR) Family

G protein-coupled receptors (GPCRs) constitute a large family involved in various types of signal transduction pathways triggered by hormones, odorants, peptides, proteins, and other types of ligands. The family is so diverse that many members lack apparent sequence similarity, although they all span the cell membrane seven times with an extracellular N- and a cytosolic C-terminus. Structure clustering of the predicted models for the 907 human GPCRs (5% of the total proteins encoded by the genome) suggests that GPCRs with similar structures tend to belong to a similar functional class, even when their sequences are diverse (Zhang et al. 2006). Wistrand et al. (2006) analyzed a divergent set of GPCRs and found distinct loop length patterns and differences in amino acid composition between cytosolic loops, extracellular loops, and membrane regions.  Multiple high resolution GPCR structures have confirmed some features predicted by the original rhodopsin-based models, and they reveal ligand-binding modes and critical aspects of the receptor activation process (Audet and Bouvier 2012).  At least some members of this family (e.g., 9.A.14.7.3) and at least some of the ionotropic ligand binding receptors (e.g., LIC; TC# 1.A.10.1.10) share an ANF receptor family ligand binding region/domain (M. Saier, unpublished observation). Interestingly, class A GPCRs appear to harness the energy of the transmembrane sodium potential to increase their sensitivity and selectivity (Shalaeva et al. 2019). This suggests, but does not prove a role in Na+ transport. GPCRs and their associated proteins play important roles in the development of cellular senescence (Santos-Otte et al. 2019).

Menon et al. (2011) demonstrated that opsin and rhodopsin are ATP-independent phospholipid flippases in photoreceptor discs. Reconstitution of opsin into large unilamellar vesicles promotes rapid flipping of phospholipid probes across the vesicle membrane. Subsequent work demonstrated that several other G-protein receptors (β1-adrenergic receptors (TC# 9.A.14.3.11), β2-adrenergric receptors (TC# 9.A.14.3.5) and adenosine A2A receptors (TC# 9.A.14.3.8) scramble lipids (Menon et al. 2011; Goren et al. 2014; Ernst and Menon 2015).  It should be noted that all of the G-protein receptors integrate into the endoplasmic reticulum (ER) before entering secretory vesicles for export to the plasma membrane, and thus, they may serve as phospholipid flippases in the ER as well as the plasma membrane (Goren et al. 2014). Cholesterol interaction motifs in G protein-coupled receptors have been reviewed (Sarkar and Chattopadhyay 2020). Phospholipid scrambling by G protein-coupled receptors has been reviewed (Khelashvili and Menon 2021). Membrane lipids are an integral part of transmembrane allosteric sites in GPCRs as has been established with the cannabinoid CB1 receptor bound to a negative allosteric modulator, ORG27569, and analogs (Obi and Natesan 2022).

Close to the retinal ligand in rhodopsin, several water molecules help to organise a functionally important hydrogen bond network that undergoes significant changes during photo-activation (Lesca et al. 2018). Such water-mediated networks are critical for ligand binding to other GPCRs, and they are becoming increasingly important in drug discovery. GPCRs also contain a partially conserved water mediated hydrogen bond network that stabilises the ground state of the receptor, and rearrangement of this network leads to stabilization of the active state (Lesca et al. 2018).

Crystal structures are available for rhodopsin, adrenergic receptors, and adenosine receptors in both inactive and activated forms, as well as for chemokine, dopamine, and histamine receptors in inactive conformations. Katritch et al. (2012) reviewed common structural features, outlined the scope of structural diversity of GPCRs at different levels of homology, and briefly discussed the impact of the structures on drug discovery. A distinct modularity is observed between the extracellular (ligand-binding) and intracellular (signaling) regions.  GPCRs comprise a consitutent family of the TOG superfamily which includes microbial rhodopsins (TC# 3.E.1) (Yee et al. 2013), and the conclusion of homology for members of these two families has been confirmed (Shalaeva et al. 2015). GPCRs and many other channel and transport proteins bind cholesterol to their intramembrane protein surfaces (Lee 2018). The dynamic aspects related to function have been considered (Wang et al. 2018).

In the retinal binding pocket of rhodopsin, a Schiff base links the retinal ligand covalently to the Lys296 side chain. Light transforms the inverse agonist 11-cis-retinal into the agonist all-trans-retinal, leading to the active Meta II state. Crystal structures of Meta II and the active conformation of the opsin apoprotein revealed two openings of the 7-transmembrane (TM) bundle towards the hydrophobic core of the membrane, one between TMS1/TMS7 and one between TMS5/TMS6, respectively. Computational analysis revealed a putative ligand channel connecting the openings and traversing the binding pocket. Single amino acids lining the channel were replaced, and 11-cis-retinal uptake and all-trans-retinal release were measured (Piechnick et al., 2012). Most mutations slow or accelerate both uptake and release, often with opposite effects, and mutations closer to the Lys296 active site show larger effects. The mutations do not probe local channel permeability but affect global protein dynamics, with the focal point in the ligand pocket. Piechnick et al. (2012) proposed a model for the retinal/receptor interaction in which the active receptor conformation sets the open state of the channel for 11-cis-retinal and all-trans-retinal, with positioning of the ligand at the active site as the kinetic bottleneck. Although other G protein-coupled receptors lack the covalent link to the protein, the access of ligands to their binding pocket may follow similar schemes. 

Rhodopsin contains a pocket within its seven TMSs which bears the inactivating 11-cis-retinal bound by a protonated Schiff-base to Lys296 in TMS7. Light-induced 11-cis-/all-trans-isomerization leads to the Schiff-base deprotonated active Meta II intermediate. With Meta II decay, the Schiff-base bond is hydrolyzed, all-trans-retinal is released from the pocket, and the apoprotein opsin reloads with new 11-cis-retinal. The crystal structure of opsin in its active Ops* conformation provides the basis for computational modeling of retinal release and uptake. The ligand-free 7 TMS bundle of opsin opens into the hydrophobic membrane layer through openings A (between TM1 and 7) and B (between TM5 and 6). A continuous channel through the protein connects these two openings and has in its central part the retinal binding pocket. The channel traverses the receptor over a distance of ca. 70 Å and is between 11.6 and 3.2 Å wide. Both openings are lined with aromatic residues, but the central part is polar. Four constrictions within the channel are so narrow that they must stretch to allow passage of the retinal beta-ionone-ring. Constrictions are at openings A and B, respectively, and at Trp265 and Lys296 within the retinal pocket.  Unidirectional passage may involve uptake of 11-cis-retinal through A and release of photolyzed all-trans-retinal through B (Hildebrand et al. 2009).

Ion Channel-Coupled Receptors (ICCRs) are artificial proteins comprised of a G protein-coupled receptor and a fused ion channel, engineered to couple channel gating to ligand binding. These biological entities have potential use in drug screening and functional characterization, in addition to providing tools in the synthetic biology repertoire as synthetic K+-selective ligand-gated channels. The ICCR concept has been validated with fusion proteins between the K+ channel Kir6.2 and muscarinic M2 or dopaminergic D2 receptors. Caro et al. (2011) extended the concept to the longer β2-adrenergic receptor which, unlike M2 and D2 receptors, displayed barely detectable surface expression and did not couple to Kir6.2 when unmodified. However, a Kir6.2-binding protein, the N-terminal transmembrane domain of the sulfonylurea receptor, greatly increased plasma membrane expression of β2 constructs.

Odorant and taste receptors account for over half of the GPCR repertoire in man. These receptors are widely expressed throughout the body and function beyond the oronasal cavity - with roles including nutrient sensing, autophagy, muscle regeneration, regulation of gut motility, protective airway reflexes, bronchodilation, and respiratory disease. Foster et al. 2013 summarized the evidence for expression and function of odorant and taste receptors in tissues beyond the nose and mouth. 

The murine cytomegalovirus (MCMV) M78 protein (TC# 9.B.14.18.1) is a member of the β-herpesvirus 'UL78 family' of seven transmembrane receptors (7TMRs). These receptors are required for efficient cell-cell spread of their respective viruses in tissue culture, and M78 knockout viruses are attenuated for replication in vivo. M78 forms dimers, a property common to several cellular 7TMRs. M78 traffics to the cell surface, but is rapidly and constitutively endocytosed. M78 co-loclaizes with markers for both the clathrin-dependent and lipid raft/caveolae-mediated internalization pathways. In MCMV-infected cells, the subcellular localization of M78 is modified during the course of infection, which may be related to the incorporation of M78 into the virion envelope during the course of virion maturation (Sharp et al. 2009). The 7 TMS beta-Herpesvirus  M78 Protein (UL78) (TC# 9.A.14.18.1) Family is a subfamily of the GPCR family within the TOG superfamily. 

Structural studies have revealed that inactive rhodopsin-like class A GPCRs (Franco et al. 2016; Cong et al. 2017) harbor a conserved binding site for Na+ ions in the center of their transmembrane domain, accessible from the extracellular space. Vickery et al. 2017 showed that the opening of a conserved hydrated channel in activated state receptors allows the Na+ to egress from its binding site into the cytosol. Coupled with protonation changes, this ion movement occurs without significant energy barriers, and can be driven by physiological transmembrane ion and voltage gradients. They proposed that Na+ ion exchange with the cytosol is a key step in GPCR activation, and that this transition locks receptors in long-lived active-state conformations (Vickery et al. 2017). Thus, while some GPCRs are lipid flippases, class A GPCRs are ion channels, and some GPCRs may function as water channels. Opsin may also be capable of transporting retinal across the membrane. 

Rhodopsins are photoreceptive proteins and key tools in optogenetics (Kandori 2020). Although rhodopsin was originally named as a red-colored pigment for vision, the modern meaning of rhodopsin encompasses photoactive proteins containing a retinal chromophore in animals and microbes. Animal and microbial rhodopsins respectively possess 11-cis and all-trans retinal, respectively. As cofactors bound with their animal and microbial rhodopsin (seven transmembrane alpha-helices) environments, 11-cis and all-trans retinal undergo photoisomerization into all-trans and 13-cis retinal forms as part of their functional cycle. While animal rhodopsins are G protein coupled receptors, the function of microbial rhodopsins is highly divergent. Many of the microbial rhodopsins are able to transport ions in a passive or an active manner. These light-gated channels or light-driven pumps represent the main tools for respectively effecting neural excitation and silencing in the emerging field of optogenetics (Kandori 2020).

Transmembrane receptors, of which GPCRs are the largest group, act as cellular antennae that  interpret information from the extracellular environment. Extracellular vesicles (EVs) are nanocarriers that can transport functionally competent transmembrane receptors, ligands, and a cargo of signal proteins. Roles for EVs in GPCR signal transduction have been reviewed (Bebelman et al. 2020). Their relevance to current GPCR and EV paradigms were discussed. GPCRs can be labeled and identified using tetrafunctional probes, consisting of (1) a ligand of interest, (2) 2-aryl-5-carboxytetrazole (ACT) as a photoreactive group, (3) a hydrazine-labile cleavable linker, and (4) biotin for enrichment (Miyajima et al. 2020).

Class A (rhodopsin-like) G protein-coupled receptors (GPCRs) are constitutive phospholipid scramblases as evinced after their reconstitution into liposomes. Yet phospholipid scrambling is not detectable in the resting plasma membrane of mammalian cells that is replete with GPCRs. Morra et al. 2022 considered whether cholesterol limits the ability of GPCRs to scramble lipids. A previous Markov State Model (MSM) analysis of molecular dynamics simulations of membrane-embedded opsin indicated that phospholipid headgroups traverse a dynamically revealed hydrophilic groove between TMSs 6 and 7 while their tails remain in the bilayer. Comparative MSM analyses of 150-mus simulations of opsin in cholesterol-free and cholesterol-rich membranes revealed that cholesterol inhibits phospholipid scrambling by occupying the TMS 6/7 interface and stabilizing the closed groove conformation while itself undergoing flip-flop. This mechanism may explain the inability of GPCRs to scramble lipids at the plasma membrane (Morra et al. 2022).

Generalized transport reactions catalyzed by opsin and/or certain other GPCRs are:


lipid (inner leaflet) ⇌ lipid (outer leaflet)


Na+ (out) ⇌ Na+ (in)

retinal (out) ⇌ retinal (in)

water (out) ⇌ water (in)


This family belongs to the NEAT/Basigin Chaparone (NBC) Superfamily.



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TC#NameOrganismal TypeExample

Long wave-sensitive opsin (red cone photoreceptor pigment). Phosphorylated on Thr and Ser in the C-terminal region. Defects cause color blindness (protanopia). Catalyzes phospholipid flipping (Menon et al., 2011).


Opsin of Homo sapiens (P04000)


Opsin of the green sea urchin


Opsin of Strongylocentrotus droebachiensis


G-protein coupled receptor 161, Gpr161 of 529 aas.  Key negative regulator of Shh signaling and the sonic hedgehog pathway via cAMP signaling.  Shh signalling promotes the processing of GLI3 into GLI3R during neural tube development (Mukhopadhyay et al. 2013).


Gpr161 of Homo sapiens


Rhodopsin of 359 aas and 7 TMSs, Rho or Zfo2.  Light activated retinal release has been studied (Morrow and Chang 2015).


Zfo2 of Danio rerio (Zebrafish) (Brachydanio rerio)


Neurotensin receptor (β group of peptide-activated G-protein receptors) of 426 aas and 7 TMSs. Receptor for the neuromedin-U and neuromedin-S neuropeptides (Raddatz et al. 2000;  Krumm and Grisshammer 2015).

Nmur1 of Homo sapiens


Neurotensin receptor type 1, Ntr1, of 418 aas and 7 TMSs.  G-protein coupled receptor for the tridecapeptide neurotensin (NTS). Signaling is effected via G proteins that activate a phosphatidylinositol-calcium second messenger system. Signaling leads to the activation of downstream MAP kinases and protects cells against apoptosis (Da Costa et al. 2013).

Ntr1 of Homo sapiens


Zinc receptor, GPR39 of 453 aas and 7 TMSs.  It  localizes mainly to the sperm tail. Zn2+ at micromolar concentrations stimulates sperm hyperactivated motility, which is mediated by a cascade involving GPR39-adenylyl cyclase (AC)-cyclic AMP (cAMP)-protein kinase A-tyrosine kinase Src (Src)-epidermal growth factor receptor and phospholipase (Allouche-Fitoussi et al. 2018).

GPR39 of Homo sapiens


G-protein coupled receptor, GRL101-like protein of 340 aas and 7 TM

GPCR of Trichoplax sp. H2


Bovine rhodopsin of 348 aas and 7 TMSs.  It is the photoreceptor required for image-forming vision at low light intensity. Also required for photoreceptor cell viability after birth. Light-induced isomerization of 11-cis to all-trans retinal triggers a conformational change that activates signaling via G-proteins (Singhal et al. 2016; Deupi et al. 2012). The x-ray structure has been determined at high resolution, and the folding and oligomerization (Okada and Palczewski 2001; Brown and Ernst 2017). This protein is 93% identical to the human ortholog (TC# 9.A.14.1.2).

Rhodopsin of Bos tauris


RH1 rhodopsin of 310 aas and 7 TMSs. This deep sea species dwells at depths of 1 - 2 km and has 38 rhodopsins, all similar in sequence, but different so that each one absorbs only an overlapping limited range of wavelengths (Musilova et al. 2019).  This way they can detect biologically produced light in an ecosystem where no light from the sun penetrates (Pennisi 2019).

Rhodopsin of Diretmus argenteus (Silver spinyfin)


Relaxin receptor 1, RXFP1, of 757 aas and 7 C-terminal TMSs. It is a receptor for relaxins. The activity of this receptor is mediated by G proteins leading to stimulation of adenylate cyclase and an increase of cAMP. Binding of the ligand may also activate a tyrosine kinase pathway that inhibits the activity of a phosphodiesterase that degrades cAMP. H3 relaxin-mediates anti-inflammatory protection (Liu et al. 2020).

RXFP1 of Homo sapiens


Rhodopsin. Photoreceptor required for image-forming vision at low light intensity. Light-induced isomerization of 11-cis to all-trans retinal triggers a conformational change leading to G-protein activation and release of all-trans retinal. The tetraspanning peripherin-2 (TC# 8.A.40.1.2) links rhodopsin to a cyclic nucleotide-dependent channel (TC# 1.A.1.5.3) in the outer segments of rod photoreceptors.  The G266D retinitis pigmentosa mutation in TMS4 of rhodopsin abolishes binding of peripherin-2 and prevents association with the CNGA1/CNGB1a subunits present in the complex (Becirovic et al. 2014).  A channel through opsin, responsible for the passage of retinal from and to its central site where it forms a Schiff's base with a lysine in TMS7 has been proposed (Hildebrand et al. 2009). Blankenship et al. 2015 presented the 2.3-A resolution structure of native source rhodopsin stabilized in a conformation competent for G protein binding. An extensive water-mediated hydrogen bond network linking the chromophore binding site to the site of G protein binding was observed, providing connections to conserved motifs essential for GPCR activation.  Both Opsin and Rhodopsin serve as phospholipid flippases (scramblases) and thus have been implicated in photoreceptor disc membrane homeostasis (Menon et al. 2011; Goren et al. 2014; Ernst and Menon 2015Wang et al. 2018). One particular conformation of rhodopsin is an open channel connecting the ligand binding site with the membrane and the intradiscal lumen of rod outer segments. Sufficient in size, the passageway permits the exchange of hydrophobic ligands such as retinal (Mattle et al. 2018). G protein-coupled receptors such as rhodopsin interact with hydrophobic ligands that probably enter their binding pockets through transmembrane pores (Tian et al. 2022).


Rhodopsin of Homo sapiens (P08100)


Neurotensin receptor-2, NTR2 or NTR3, of 410 aas and 7 TMSs. Sortilin/NTSR3 (membrane-bound and soluble (extracellular) forms) are involved in many pathophysiological processes from cancer development to cardiovascular diseases, Alzheimer's disease, diabetes, and major depression (Mazella 2022).

NTR2 of Homo sapiens


Melatonin receptor type 1A, or MT1 of 350 aas and 7 TMSs.  Although the MT1 and 5-HT receptors have similar endogenous ligands, and agomelatine acts on both receptors, the receptors differ markedly in the structure and composition of their ligand pockets; in MT1, access to the ligand pocket is tightly sealed from solvent by extracellular loop 2, leaving only a narrow channel between transmembrane helices IV and V that connects it to the lipid bilayer (Stauch et al. 2019). The binding site is extremely compact, and ligands interact with MT1 mainly by strong aromatic stacking with Phe179 and auxiliary hydrogen bonds with Asn162 and Gln181. Free-energy simulations support a lipophilic binding route for melatonin receptors (Elisi et al. 2021).


Melatonin receptor type 1A of Homo sapiens (P48039)


Thyrotropin-releasing hormone receptor


Thyrotropin-releasing hormone receptor of Homo sapiens (P34981)


Follicle-stimulating hormone receptor


Follicle-stimulating hormone receptor of Homo sapiens (P23945)


The ghrelin receptor, a peptide-activated (Growth hormone secretagogue) class A GPCR, GHS-R or GH-releasing peptide receptor (Mary et al., 2012). Intestinal dysmotility is associated with decreased ghrelin and vimentin expression and loss of intestinal cells of Cajal (Sukhotnik et al. 2021).


Ghrelin receptor of Homo sapiens (Q92847)


Photoreceptor melanopsin implicated in non-image formation in response to light.


Melanopsin of Xenopus laevis


Photoreceptor melanopsin that regulates circadian rhythms (Melyan et al. 2005).


Melanopsin of Homo sapiens


Rhadbomeric opsin of the clam worm.


Rhabdomeric opsin of Platynereesis dumerilii


TC#NameOrganismal TypeExample

Gonadotropin-releasing hormone receptor


Gonadotropin-releasing hormone receptor of Homo sapiens (P30968)


Renal vasopressin receptor V1b (Hagiwara et al. 2013).


Vasopressin receptor V1b of Homo sapiens


Vasopressin receptor 2, AVPR2 of 371 aas and 7 TMSs. Pharmacochaperones post-translationally enhance cell surface expression  of V2 by increasing the conformational stability of wild-type and mutant vasopressin V2 receptors (Wüller et al. 2004).


AVPR2 of Homo sapiens


Dimeric oxytosin receptor, OxtR, of 389 aas and 7 TMSs. Superpotent behavior follows from the binding of oxytosin receptor-specific bivalent ligands to dimeric receptors based on a TMS1-TMS2 interface, and in this arrangement, only analogues with a well-defined spacer length (approximately 25 Å) precisely fit inside a channel-like passage between the two protomers of the dimer (Busnelli et al. 2016). The oxytocin receptor (OXTR) is involved in parturition and lactation of mammals as well as  their emotional and social behaviors. Cholesterol acts on OXTR as an allosteric modulator, inducing a high-affinity state for orthosteric ligands. Stable binding of cholesterol to the receptor when it adopts an orthosteric ligand-bound state  preserves the cholesterol-dependent activity of the receptor (Lemel et al. 2021).

OxtR of Homo sapiens


G-protein coupled receptor, NPSR1, for neuropeptide S (NPS) and promotes mobilization of intracellular Ca2+ stores (Bernier et al. 2006). It also inhibits cell growth in response to NPS binding (Vendelin et al. 2005). It is involved in the pathogenesis of asthma and other IgE-mediated diseases (Xu et al. 2004; Bernier et al. 2006).

NPSR1 of Homo sapiens


Arginine vasotocin receptor of 419 aas and 7 TMSs (Kang et al. 2019). The vasotocin receptor family is homologous to mammalian vasopressin G-protein coupled receptors (Jayanthi et al. 2014).It controls water flow via aquaporin-2 in the kidney (Yang et al. 2004).

Arginine vasotocin receptor of Gallus gallus


TC#NameOrganismal TypeExample

G-protein-coupled receptor, GH10049p


GH10049p of Drosophila melanogaster (Q8MSJ2)


G-protein-coupled receptor, GPCR, family C, group 5 member C, isoform a


GPCR of Homo sapiens (Q9NQ84)


TC#NameOrganismal TypeExample

Vomeronasal type-1 receptor 1 of 353 aas and 7 TMSs.


Vomeronasal type-1 receptor 1 of Homo sapiens (Q9GZP7)


Vomeronasal 1 receptor of 300 aas and 7 TMSs.

Vomeronasal 1 receptor of Oryctolagus cuniculus


Vomeronasal type-1 receptor 3-like of 321 aas and 7 TMSs.

Vomeronasal receptor of Cyprinodon variegatus


Vomeronasal type-1 receptor of 341 aas and 7 TMSs.

Vomeronasal receptor of Equus asinus


TC#NameOrganismal TypeExample

Type-1a angiotensin II receptor of 395 aas and 7 or 8 TMSs, AGTR1(A and B), AT2R1, AT2R1B.  A single mutation in the amphipahtic helix 8 enhances its transport and signalling (Zhu et al. 2015).


Type-1 angiotensin II receptor of Homo sapiens (P30556)


The apelin hormone receptor (angiotensin receptor; GPCR APJ; GPCR HC11) of 380 aas.  The human apelin (77 aas) receptor is coupled to G proteins that inhibit adenylate cyclase activity.
It plays a role in various processes in adults such as regulation of blood pressure, heart contractility, and heart failure. During heart formation, it acts as a receptor for elabela hormone (ELA). It influences cell movement during embryonic development and serves as an alternative coreceptor with CD4 for HIV-1 infection (Pauli et al. 2014); it may be involved in the development of AIDS dementia.


Apelin receptor of Homo sapiens


Uncharacterized protein of 317 aas and 7 TMSs.  Shows sequence similarity to proteins in 9.B.190.


UP of Danio rerio (Zebrafish) (Brachydanio rerio)


Proteinase-activated receptor-2 of 397 aas and 7 TMSs (δ group), F2RL1, GPR11, PAR2, or PAR-2.  Receptor for trypsin and trypsin-like enzymes coupled to G proteins. Its function is mediated through the activation of several signaling pathways including phospholipase C (PLC), intracellular calcium, mitogen-activated protein kinase (MAPK), I-kappaB kinase/NF-kappaB and Rho. It can also be transactivated by cleaved F2R/PAR1. It is involved in modulation of inflammatory responses and regulation of innate and adaptive immunity, and it acts as a sensor for proteolytic enzymes generated during infection (Krumm and Grisshammer 2015). PAR-2, the second member of the G protein-coupled PAR family, is irreversibly activated by trypsin or tryptase and then targeted to lysosomes for degradation. Intracellular presynthesized receptors stored at the Golgi apparatus repopulate the cell surface after trypsin stimulation, thereby leading to rapid resensitization to trypsin signaling (Luo et al. 2007).  p24A, a type I transmembrane protein, controls ARF1-dependent resensitization of PAR-2 by influencing receptor trafficking (Luo et al. 2007).


PAR2 of Homo sapiens


Neuropeptides B/W receptor type 2, Npbwr2 of 333 aas and 7 TMSs. Of the γ-group.  Interacts specifically with a number of opioid ligands. Receptor for neuropeptides B and W, which may be involved in neuroendocrine system regulation, food intake and the organization of other signals (Krumm and Grisshammer 2015).

Npbwr2 of Homo sapiens


The KiSS receptor (KiSSR) or G-protein receptor 54.  Receptor for metastin (kisspeptin-54 or kp-54), a C-terminally amidated peptide of KiSS1. KiSS1 is a metastasis suppressor protein that suppresses metastases in malignant melanomas and in some breast carcinomas without affecting tumorigenicity. Kisspeptin and GABA interact to modulate secretion and reproduction (Di Giorgio et al. 2019).


KiSS receptor of Homo sapiens


Chemokine-like receptor 1, Cmklr1, of 373 aas and 7 TMSs.  Receptor for the chemoattractant, adipokine chemerin/RARRES2, and for the omega-3 fatty acid-derived molecule, resolvin E1. Interaction with RARRES2 induces activation of intracellular signaling molecules leading to multifunctional effects, e.g., reduction of immune responses, enhancment of adipogenesis and angionesis. Resolvin E1 down-regulates cytokine production in macrophages. Positively regulates adipogenesis and adipocyte metabolism (Krumm and Grisshammer 2015).


The P2Y purinoreceptor 2, P2Y2 of 377 aas and 7 TMSs.  Receptor for ATP and UTP coupled to G-proteins that activate a phosphatidylinositol-calcium second messenger system. The affinity range is UTP = ATP > ATP-gamma-S >> 2-methylthio-ATP = ADP.  Plays a role in shedding (Pupovac and Sluyter 2016).  There are eight mammalian P2Y receptor subtypes (P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13, and P2Y14), and they play a variety of roles in cell physiology (von Kügelgen and Hoffmann 2016).  The 3-d x-ray structure of a P2Y2 receptor is known (Jacobson et al. 2015).  Antagonists stabilize an ionic lock within the P2T1 receptor, but binding of ADP breaks this ionic lock, forming a continuous water channel that leads to P2Y1 receptor activation (Yuan et al. 2016).

P2Y2 of Homo sapiens


Chemokine receptor type 4, CXCR4 of 352 aas and 7 TMSs.  The majority of essential residues form a continuous intramolecular signaling chain through the transmembrane helices.  This chain connects chemokine binding residues on the extracellular side of CXCR4 to G protein-coupling residues on its intracellular side. Integrated into a cohesive model of signal transmission, these CXCR4 residues cluster into five functional groups that mediate (i) chemokine engagement, (ii) signal initiation, (iii) signal propagation, (iv) microswitch activation, and (v) G protein coupling. Propagation of the signal passes through a "hydrophobic bridge" on helix VI (Wescott et al. 2016).

CXCR4 of Homo sapiens


Mu-type opioid receptor of 400 aas and 7 TMSs, OprM1. Receptor for endogenous opioids such as beta-endorphin and endomorphin and for natural and synthetic opioids including morphine, heroin, DAMGO, fentanyl, etorphine, buprenorphin and methadone. Agonist binding to the receptor induces coupling to an inactive GDP-bound heterotrimeric G-protein complex and subsequent exchange of GDP for GTP in the G-protein alpha subunit leading to dissociation of the G-protein complex with the free GTP-bound G-protein alpha and the G-protein beta-gamma dimer activating downstream cellular effectors. The agonist- and cell type-specific activity is predominantly coupled to pertussis toxin-sensitive G(i) and G(o) G alpha proteins, GNAI1, GNAI2, GNAI3 and GNAO1 isoforms Alpha-1 and Alpha-2, and to a lesser extend to pertussis toxin-insensitive G alpha proteins GNAZ and GNA15. They mediate an array of downstream cellular responses, including inhibition of adenylate cyclase activity as well as both N-type and L-type calcium channels, and activation of inward rectifying potassium channels (Knapman and Connor 2015). Activation of the astrocytic μ-opioid receptor elicits fast glutamate release through TREK-1-containing K2P channel in hippocampal astrocytes (Woo et al. 2018).

OprM1 of Homo sapiens


The G-protein-coupled estrogen receptor, GPER (Gpr30; GPER1) of 375 aas and 7 TMSs.  GPER binds to 17-beta-estradiol (E2) with high affinity and aldosterone with lower affinity, leading to rapid and transient activation of numerous intracellular signaling pathways. Activating GPR30 by estrogen results in intracellular calcium mobilization and synthesis of phosphatidylinositol 3,4,5-trisphosphate in the nucleus. Thus, GPR30 represents an intracellular transmembrane estrogen receptor that may contribute to normal estrogen physiology as well as pathophysiology. It stimulates cAMP production, calcium mobilization and tyrosine kinase Src (Gros et al. 2013; Gaudet et al. 2015).

GPER of Homo sapiens


Cysteinyl leukotriene receptor 1


Cysteinyl leukotriene receptor 1 of Homo sapiens (Q9Y271)


Prosaposin receptor, Gpr37 of 613 aas and 7 TMSs. Receptor for the neuroprotective and glioprotective factor, prosaposin. Ligand binding induces endocytosis, followed by an ERK phosphorylation cascade (Meyer et al. 2013).

Prosaposin receptor of Homo sapiens


Prorelaxin receptor RXFP3 (RLN3R1, SALPR) of 469 aas and 7 TMSs.  Relaxin is an ovarian hormone that acts with estrogen to produce dilatation of the birth canal in many mammals. Cholesterol modulates the binding properties of human RXFP3 with its ligands, enhancing that of some, and decreasing that of others (Wang et al. 2018).

RXFP3 of Homo sapiens


P2Y1 purinoceptor of 373 aas and 7 TMSs.  Receptor for extracellular adenine nucleotides such as ATP and ADP. In platelets binding to ADP leads to mobilization of intracellular calcium ions via activation of phospholipase C, a change in platelet shape, and probably to platelet aggregation (Jin et al. 1998).

P2Y1 of Homo sapiens


Receptor for somatostatin-14 and -28 of 418 aas and 7 TMSs, SSTR3. This receptor is coupled via pertussis toxin sensitive G proteins to inhibition of adenylyl cyclase (Yamada et al. 1992). Motility and signaling functions of the primary cilium require a unique protein and lipid composition that is determined by gating mechanisms localized at the base of the cilium, and SSTR3 plays a direct role (Takao et al. 2017). B9D1, AHI1, and the N termini of NPHP4 and NPHP5 interact with SSTR3 and thus spatially map to the outer region of the ciliary gating zone.


SSTR3 of Homo sapiens


Long neuropeptide F receptor (NPFR) isoform 1 of 390 aas and 7 TMSs. NPFR may play roles within the CNS in digestion and possibly egg production and/or egg development in R. prolixus (Sedra et al. 2018).

NPFR of Rhodnius prolixus


G-protein coupled receptor 139, GPR139, GPRG1 or PGR3, of 353 aas and 7 TMSs.  It is an orphan receptor that seems to act through a G(q/11)-mediated pathway.  GPR139 and the dopamine D2 receptor co-express in the same cells of the brain and may functionally interact (Wang et al. 2019). Loss of GPR139 enhanced effects of morphine in mice but reduced withdrawal effects (Wang et al. 2019). It is a regulator of opioid receptors (Lindsay and Scherrer 2019).


GPR139 of Homo sapiens


C5a anaphylatoxin chemotactic receptor 1 of 350 aas and 7 TMSs. Receptor for the chemotactic and inflammatory peptide anaphylatoxin C5a (Robertson et al. 2018).

C5a anaphylatoxin receptor of Homo sapiens


Receptor for bradykinin of 392 aas and 7 TMSs. It is associated with G proteins that activate a phosphatidylinositol-calcium second messenger system (Tang et al. 2018).

Bradykinin receptor of Homo sapiens


Putative biopolymer transport system, comprising a probable proton channel, ExbB/ExbD (Slr0677/Slr0678). These proteins energize one or more outer membrane receptors (1.B.14); probably involved in iron-siderophore uptake. ExbD interacts directly with TonB (TC# 2.C.1.3.1) (Qiu et al. 2018).

ExbB/ExbD of Synechocystis sp. (strain PCC 6803 / Kazusa)


Free fatty acid receptor-4, FFAR4, or GPR120, of 361 aas and 7 TMSs. GPR120 is a long-chain fatty acid receptor that stimulates incretin hormone release from colonic endocrine cells and is implicated in macrophage and adipocyte function (Watson et al. 2012).

FFAR4 of Homo sapiens


Platelet-activating factor receptor


Platelet-activating factor receptor of Homo sapiens (P25105)


Free fatty acid receptor-1, FFAR1 or GPR40, of 300 aas and 7 TMSs. G-protein coupled receptor for medium and long chain saturated and unsaturated fatty acids that plays an important role in glucose homeostasis (Briscoe et al. 2003). Fatty acid binding increases glucose-stimulated insulin secretion, and may also enhance the secretion of glucagon-like peptide 1 (GLP-1) (Suckow et al. 2014). May also play a role in bone homeostasis; receptor signaling activates pathways that inhibit osteoclast differentiation (Philippe et al. 2016). Ligand binding leads to a conformation change that triggers signaling via G-proteins that activate phospholipase C, leading to an increase of the intracellular calcium concentration (Li et al. 2020). The receptor is strongly activated by gamma-linolenic acid, while myristate gives a lower response. It is also activated by phytanic acid and pristanic acid (Kruska and Reiser 2011).

FFAR1 of Homo sapiens


Platelet P2Y purinoceptor 12, P2Y12 or P2YR12, of 342 aas and 7 TMSs. It is a receptor for ADP and ATP coupled to G-proteins that inhibit the adenylyl cyclase second messenger system. It is not activated by UDP and UTP. It is required for normal platelet aggregation and blood coagulation (Hollopeter et al. 2001). Clopidogrel is a potent antithrombotic drug that targets the P2Y12 receptor and inhibits ADP-induced platelet aggregation (Herbert and Savi 2003). The structure has been determined (Zhang et al. 2014) with and without agonist (Zhang et al. 2014).

P2Y12 of Homo sapiens (Human)


Kappa-opioid receptor, KOR, of 380 aas and 7 TMSs.  Sperm-specific protein changes occur downstream of KOR in human spermatozoa (Urizar-Arenaza et al. 2019). It functions as a receptor for endogenous alpha-neoendorphins and dynorphins, but has low affinity for beta-endorphins. It also functions as a receptor for the psychoactive diterpene salvinorin A. Ligand binding causes a conformation change that triggers signaling via G proteins and modulates the activity of down-stream effectors, such as adenylate cyclase (Wu et al. 2012).

Kappa opioid receptor, KOR, of Homo sapiens


Neuropeptide Y receptor type 2, NPYR2, of 381 aas and 7 TMSs. It is a receptor for neuropeptide Y and peptide YY. The rank order of affinity of this receptor for pancreatic polypeptides is PYY > NPY > PYY (3-36) > NPY (2-36) > [Ile-31, Gln-34] PP > [Leu-31, Pro-34] NPY > PP, [Pro-34] PYY and NPY free acid. Neuropeptide Y (NPY) and NPY receptors are widely expressed in the central nervous system, including the retina. Retinal cells express this peptide and its receptors (Y1, Y2, Y4 and/or Y5), and NPY is expressed in the retina of various mammalian and non-mammalian species. Its early expression strongly suggests that NPY may be involved in the development of retinal circuitry. NPY inhibits the increase in [Ca2+]i, triggered by elevated KCl in retinal neurons, due to inhibition of Ca2+ channels, and  it protects retinal neural cells against toxic insults while inducing the proliferation of retinal progenitor cells. Santos-Carvalho et al. 2014 reviewed the roles of NPY in the retina, specifically proliferation, neuromodulation and neuroprotection. Alterations in the NPY system in the retina might contribute to the pathogenesis of retinal degenerative diseases, such as diabetic retinopathy and glaucoma.

YPN2 of Homo sapiens


The Duffy antigen, DARC or ACKR1, FY, GPD, of 336 aas and 7 TMSs. It is an atypical chemokine receptor that controls chemokine levels and localization via high-affinity chemokine binding that is uncoupled from classic ligand-driven signal transduction cascades, resulting instead in chemokine sequestration, degradation, or transcytosis. It is also known as interceptor (internalizing receptor) or chemokine-scavenging receptor or chemokine decoy receptor. Almost the entire populations of DARC and three other transmembrane proteins are immobilized by either the incorporation within large multiprotein complexes or entrapment within the protein network of the cortical spectrin cytoskeleton (Kodippili et al. 2020).


DARC of Homo sapiens


Atypical chemokine receptor, C5aR2, that controls chemokine levels and localization via high-affinity chemokine binding that is uncoupled from classic ligand-driven signal transduction cascades, resulting instead in chemokine sequestration, degradation, or transcytosis. It is also known as interceptor (internalizing receptor) or chemokine-scavenging receptor or chemokine decoy receptor. Acts as a receptor for chemokines including CCL2, CCL3, CCL3L1, CCL4, CCL5, CCL7, CCL8, CCL11, CCL13, CCL17, CCL22, CCL23, CCL24, SCYA2/MCP-1, SCY3/MIP-1-alpha, SCYA5/RANTES and SCYA7/MCP-3. Upon active ligand stimulation, it activates a beta-arrestin 1 (ARRB1)-dependent, G protein-independent signaling pathway that results in the phosphorylation of the actin-binding protein cofilin (CFL1) through a RAC1-PAK1-LIMK1 signaling pathway. Activation of this pathway results in up-regulation of ACKR2 from endosomal compartment to cell membrane, increasing its efficiency in chemokine uptake and degradation (McKimmie et al. 2013; Borroni et al. 2013).

D6R of Homo sapiens


Somatostatin receptor type 1, SSTR1, of 391 aas and 7 TMSs. Prostate-specific membrane antigen, Lutetium-177, is a transmembrane protein found predominately on the prostate epithelium and is expressed at high levels in prostate cancer. It's properties have been reviewed (Jia et al. 2022).

SSTR1 of Homo sapiens


Protease-activated receptor_1 of 425 aas and 7 TMSs, PAR1, F2R, CF2R. It activates the KCNN3 channel. Dextran sodium sulfate (DSS) treatment causes loss of transient relaxations due to downregulation of SK3 channels (TC#1.A.1.16.7) and may increase contractile responses due to increased Ca2+ sensitization of smooth muscle cells via PAR1 activation (Sung et al. 2022).


PAR1 of Homo sapiens


G-protein coupled receptor 81


G-protein coupled receptor 81 of Homo sapiens (Q9BXC0)


Leukotriene B4 receptor 1


Leukotriene B4 receptor 1 of Homo sapiens (Q15722)


Melanin-concentrating hormone receptor 1

AnimalsMCHR1 of Homo sapiens
9.A.14.13.7Mas-related G-protein coupled receptor member F (Mas-related gene F protein) (G-protein coupled receptor 140) (G-protein coupled receptor 168)AnimalsMRGPRF of Homo sapiens

G-protein-coupled receptor GPR35.  Agonists include the tryptophan metabolite kynurenic acid, the synthetic ligand zaprinast and two thiazolidinediones.  Agonist activation involves TMSIII and is transduced via Galpha(1)(3) and beta-arrestin-2 (Jenkins et al. 2011).


GPR35 of Homo sapiens


Lysophosphatidic acid receptor 4 (LPA-4; G-protein receptor 23; purinoreceptor 9 (purinurgic receptor 9), P2Y9.  The C-terminal tail directs the protein to the apical membrane of polarized epithelial cells (DuBose et al. 2013).


LPA-4 of Homo sapiens


TC#NameOrganismal TypeExample

Probable G-protein coupled receptor Mth-like 10


Probable G-protein coupled receptor Mth-like 10 of Drosophila melanogaster (Q9W0R5)


Methuselah (Mth) G-protein receptor.  Involved in biological aging and stress responses. Essential for adult survival. Required in the presynaptic motor neuron to up-regulate neurotransmitter exocytosis at larval glutamatergic neuromuscular junctions. Regulates a step associated with docking and clustering of vesicles at release sites.


Methusalah of Drosophila melanogaster


TC#NameOrganismal TypeExample

Gamma-aminobutyric acid type B receptor subunit 2


Gamma-aminobutyric acid type B receptor subunit 2 of Homo sapiens (O75899)


Probable G-protein coupled receptor CG31760


CG31760 of Drosophila melanogaster


Metabolomic GABA-B receptor, GrlE or GluPR, of 816 aas and 7 TMSs. May be involved in the early development of cAMP sensing and subsequent chemotactic responses. It is the receptor for GABA and glutamate, leading respectively to the induction or inhibition of SDF-2 formation (Anjard and Loomis 2006; Prabhu et al. 2007).


GrlE of Dictyostelium discoideum (Slime mold)


Metabolomic GABAB receptor (GABABR, GPR156, GABABL, PGR28) of 814 aas and 7 N-terminal TMSs in a 4 + 3 TMS arrangement. It plays a role in idiopathic pulmonary fibrosis (IPF), a rare  persistent lung disorder that actuates scarring of lung tissues, making breathing difficult (Mishra et al. 2021).


GABAB receptor of Homo sapiens


TC#NameOrganismal TypeExample

Frizzled-1, FZD1 of 647 aas and 8 to 11 TMSs with 1 - 4 TMSs near the N-terminus, and 7 TMSs near the C-terminus. Receptor for Wnt proteins. Most of frizzled receptors are coupled to the beta-catenin canonical signaling pathway, which leads to the activation of disheveled proteins, inhibition of GSK-3 kinase, nuclear accumulation of beta-catenin and activation of Wnt target genes. A second signaling pathway involving PKC and calcium fluxes has been seen for some family members. Association of Frizzled-6 from Drosophila melanogaster with CELSR1 (see TC# 9.A.14.6.4) is important, enabling efficient Frizzled-6 delivery to the cell surface, providing a quality-control mechanism that ensures appropriate stoichiometry of these two planar cell polarity (PCP) proteins at cell boundaries (Tang et al. 2020).


FZD1 of Homo sapiens


Frizzled-2, Fe2 of 694 aas and 7 TMSs.  Receptor for Wnt proteins. Most frizzled receptors are coupled to the beta-catenin canonical signaling pathway, which leads to the activation of disheveled proteins, inhibition of GSK-3 kinase, nuclear accumulation of beta-catenin and activation of Wnt target genes. A second signaling pathway involving PKC and calcium fluxes has been seen for some family members, but it is not yet clear if it represents a distinct pathway or can be integrated in the canonical pathway, as PKC seems to be required for Wnt-mediated inactivation of GSK-3 kinase. Both pathways seem to involve interactions with G-proteins. Required to coordinate the cytoskeletons of epidermal cells to produce a parallel array of cuticular hairs and bristles (Hsieh et al. 1999).


Fr2 of Drosophila melanogaster (Fruit fly)


Frizzled 6, FZD6 of 712 aas and 7 TMSs. FZD6  functions in multiple signal transduction pathways, for example, as a receptor in Wnt/planar cell polarity (PCP) signaling pathway for polarized cell migration and organ morphogenesis. Mutations in FZD6 have been identified in a variety of tumors (Zou et al. 2017).  Sfz6 mRNA is ubiquitously expressed, being highest in kidney and heart, and moderate in jejunum, ileum, colon, liver, and spleen.In the jejunum, FZD6 protein is more prevalent in the villus than in the crypt cells (Zou et al. 2017). FZD6 forms dimers, whose association is regulated by WNT proteins, and dimer dissociation is crucial for FZD6 signaling (Petersen et al. 2017).

FZD6 of Sus scrofa (Pig)


G-protein homologue, Smoothed; Smo; Smoh, of 787 aas and 7 TMSs (Lum and Beachy 2004). It is regulated via the Hedgehog pathway by the RND-like protein, Patched1 ((PTCH1; TC# 2.A.6.6.13) (Myers et al. 2017). The cryoEM structure of SMO bound to Patched reveals that SMO has a channel open to the membrane as well as to the extracellular cysteine-rich domain (CRD). This domain, like that in Patched, is large enough to accomodate cholesterol, so SMO could be a transporter as well as a receptor (Sommer and Lemmon 2018; Qi et al. 2018). Sterols in an intramolecular channel of Smoothened mediate Hedgehog signaling (Qi et al. 2020). SMO, a class Frizzled G protein-coupled receptor (class F GPCR), transduces the Hedgehog signal across the cell membrane. Sterols can bind to its extracellular cysteine-rich domain (CRD) and to several sites in the seven transmembrane helices (7 TMSs) of SMO. Qi et al. 2020 determined the structures of SMO-Gi complexes bound to the synthetic SMO agonist (SAG) and to 24(S),25-epoxycholesterol (24(S),25-EC). A novel sterol-binding site in the extracellular extension of TM6 was revealed to connect other sites in the 7-TMSs and CRD, forming an intramolecular sterol channel from the middle side of 7-TMSs to CRD. Additional structures of two gain-of-function variants, SMO(D384R) and SMO(G111C/I496C), showed that blocking the channel at its midpoints allows sterols to occupy the binding sites in 7-TMSs, thereby activating SMO. Thus, sterol transport through the core of SMO is a major regulator of SMO-mediated signaling. These observations shows that like other 7 TMS GPCRs, SMO is capable of transport, in this case, transporting cholesterol (Qi et al. 2020). The regulatory activities of cellular lipids and sterols has been measured during Hedgehog signaling (Deshpande and Manglik 2022).



Smoothed of Homo sapiens


Frizzled, Fz, of 468 aas and 7 TMSs, a receptor for Wnt proteins. Involved in transcriptional regulation of synapse development (Mathew et al. 2005). It is a target of insecticides (Audsley and Down 2015). Its targeting from the ER to the plasma membrane has been studied (Tang et al., 2020; PMID# 33516494).


Frizzled of Drosophila melanogaster (Fruit fly)


Protein smoothened, Smo, of 1036 aas and 7 TMSs, fairly centrally located. Glycolysis regulates Hedgehog (Hh) signalling via the plasma membrane potential, and Smo regulates this signalling (Spannl et al. 2020). The regulatory activities of cellular lipids and sterols has been measured during Hedgehog signaling (Deshpande and Manglik 2022).

Smo of Drosophila melanogaster (Fruit fly)


Secreted frizzled-related protein 1, SFRP1, FRP-1, sFRP-1, secreted apoptosis-related protein 2, SARP-2 of 314 aas and 1 TMS. It is a potential target of oral squamous cell carcinoma (OSCC) (Chen et al. 2022). Highly expressed SFRP1 is associated with membrane potential and passive transmembrane transporter activity and is mainly enriched in calcium pathway and neuroactive ligand-receptor interaction (Chen et al. 2022). Thus, SFRP1 expression provides insight into the risk and prognostic stratification in OSCC.

SFRP1 of Homo sapiens


TC#NameOrganismal TypeExample

Taste receptor type 2 member 1, TAS2.  Glutamate (bitter) taste receptor expressed in the tongue and palate epithelia.


TAS2 of Homo sapiens


Taste receptor type 2 member 4 of 299 aas and 7 TMSs, TAS2R4.

TAS2R4 of Homo sapiens


Taste receptor type 2 member 40 of 315 aas and 7 TMSs, TAS2R40.

TAS2RX of Latimeria chalumnae (West Indian ocean coelacanth)


Taste receptor type 2 of 316 aas and 7 TMSs, TR2

TR2 of Pelodiscus sinensis (Chinese softshell turtle) (Trionyx sinensis)


Taste receptor type 2 member 38 (T2R38; bitter taste receptor of 333 aas and 7 TMSs) (Gaida et al. 2016).  Activated by the bona fide ligand for T2R38, phenylthiourea (PTU), and by N-acetyl-dodecanoyl homoserine (AHL-12), a quorum sensing molecule of Pseudomonas aeruginosa. The latter is the only known natural ligand for T2R38. In response to PTU or AHL-12, key transcription factors are activated including phosphorylation of the MAP kinases p38 and ERK1/2, and upregulation of NFATc1. Increased expression of the multi-drug resistance protein 1 (ABCB1, TC# 3.A.1.201.1) is also observed, a transporter that shuttles a plethora of drugs, such as chemotherapeutics and antibiotics (Gaida et al. 2016).

Bitter taste receptor of Homo sapiens


TC#NameOrganismal TypeExample

Cytomegalovirus M78 receptor of 473 aas and 7 TMSs.  It's trafficing has been studied (Sharp et al. 2009).  This protein is a member of the β-herpesvirus 'UL78 family' of seven transmembrane receptors which are required for efficient cell-cell spread of the virus in tissue culture, and M78 knockout viruses are attenuated for replication in vivo. M78 forms dimers, a property common to several cellular 7TMR. It traffics to the cell surface but is rapidly and constitutively endocytosed.  In MCMV-infected cells, the subcellular localization of M78 is modified during the course of infection, which may be related to the incorporation of M78 into the virion envelope during the course of virion maturation (Sharp et al. 2009).

Animal virus

M78 of murine cytomegalovirus


pR78 protein of 474 aas and 7 TMSs.

Animal viruses

pR78 of Rat cytomegalovirus


Envelope protein UL78 of 431 aas and 7 TMSs.

Animal viruses

UL78 of Human cytomegalovirus (strain Toledo) (HHV-5) (Human herpesvirus 5)


Envelope protein U78 of 333 aas and 7 TMSs

Animal viruses

UL78 of Saimiriine herpesvirus 4


TC#NameOrganismal TypeExample

G-protein receptor, GPR160 of 338 aas and 8 putative TMSs. The expression level of endogenous GPR160 is associated with the pathogenesis of prostate cancer as well as apoptosis and cell cycle arrest (Zhou et al. 2016).

GPR160 of Homo sapiens


TC#NameOrganismal TypeExample

Sphingosine 1-phosphate receptor, Edg1, Edg-1, CHEDG1 or S1PR1. The 3-d structure in known (Hanson et al., 2012). The activation mechanism has been proposed (Caliman et al. 2017). It plays an important role in cell migration, probably via its role in the reorganization of the actin cytoskeleton and the formation of lamellipodia in response to stimuli that increase the activity of the sphingosine kinase, SPHK1. It is also required for normal chemotaxis toward sphingosine 1-phosphate. Finally it is involved in responses to oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine by pulmonary endothelial cells (Singleton et al. 2009; Hanson et al. 2012).


Edg-1 of Homo sapiens (P21453)


Cannabinoid receptor 1. The endocannabinoid system is widely present in the retina where it can modulate neurotransmitter release and ion channel activity (Bouchard et al. 2016). Endogenous endocannabinoids such as anandamide and 2-arachidonoyl glycerol (2AG) bind to the receptor and influence many processes including feeding, learning, memory, pain, emotions, sleep and dreams (Murillo-Rodriguez et al. 2017). Membrane lipids are integral parts of transmembrane allosteric sites in GPCRs as has been established with the cannabinoid CB1 receptor bound to a negative allosteric modulator, ORG27569, and analogs (Obi and Natesan 2022).


Cannabinoid receptor 1 of Homo sapiens (P21554)


Melanocortin receptor 4, MC4R, of 332 aas and 7 TMSs. At least 4% of childhood obesity is due to mutations in the hypothalamic MC4R which is important in the regulation of feeding behavior and body weight. MC4R activates the Galphaq/phospholipase C signaling pathway, resulting in alterations of cytoplasmic calcium in immortalized hypothalamic (GT1-1)neurons. Thus, upon agonist binding, MC4R mediates increases in intracellular calcium through the Galphaq-protein/phospholipase C dependent signaling pathway (Newman et al. 2006).  MC4R binds to two neuropeptides, α-melanocyte-stimulating hormone [αMSH] and agouti-related protein [AgRP] which exert opposing effects on downstream responses.  The 3-D structure of MC4R complexed with the cyclic peptide antogonist, SHU9119, revealed a Ca2+-binding site that influences downstream signaling (Chaturvedi and Shukla 2020). Israeli et al. 2021 presented the cryo-EM structure of the human MC4R-Gs signaling complex bound to the agonist setmelanotide, a cyclic peptide recently approved for the treatment of obesity. The work reveals the mechanism of MC4R activation, highlighting a molecular switch that initiates satiation signaling. Calcium (Ca2+) is required for agonist, but not antagonist, efficacy (Israeli et al. 2021).


MC4R of Homo sapiens (P32245)


ACTH-specific receptor, MC2R, in the melanocortin receptor family that includes MC1R - MC5R which recognize different melanocortin peptides.  Domains responsible for specific membrane transport and lignad specificity in MC2R have been identified (Fridmanis et al. 2010). MC accessory protein (MRAP) facilitates MC2 receptor trafficking and allows properly localized receptor to bind ACTH and consequently signal (Sebag and Hinkle 2009).


MC2R of Homo sapiens


Lysophosphosphatidic acid (LPA) receptor, Edg4, of 351 aas and 7 TMSs.  Mediates fibroblast chemotaxis (Ren et al. 2014), and forms a coplex with CFTR (3.A.1.202.1) (Zhang et al. 2017).

Edg4 of Homo sapiens


Cannabinoid receptor 2, CNR2. The endocannabinoid system is widely present in the retina where it can modulate neurotransmitter release and ion channel activity (Bouchard et al. 2016). Endogenous endocannabinoids such as anandamide and 2-arachidonoyl glycerol (2AG) bind to the receptor and influence many processes including feeding, learning, memory, pain, emotions, sleep and dreams (Murillo-Rodriguez et al. 2017).  It plays a vital role in regulation of immune response, inflammation, pain, and other metabolic processes. Its 3-d structure has been studied by NMR (Yeliseev and Gawrisch 2017). EPR studies revealed that higher mobility was observed in the center of internal loop 3,  and a structural change occurs between agonist vs. inverse agonist-bound CB2 in the extracellular tip of transmembrane helix 6 (Yeliseev et al. 2021).

CNR2 of Homo sapiens


G-protein coupled receptor, GPR3 or ACCA, of 330 aas and 7 TMSs.  It is an orphan receptor with constitutive G(s) signaling activity that activates cyclic AMP. It has a potential role in modulating a number of brain functions, including behavioral responses to stress, amyloid-beta peptide generation in neurons and neurite outgrowth. It maintains meiotic arrest in oocytes.  It is the most cold-induced G-coupled receptor in both brown and beige thermogenic adipose tissues. It has high basal Gs-coupled activity in the absence of an exogenous ligand (Sveidahl Johansen et al. 2021). It mimicks the cold induction of Gpr3 triggered cAMP production, activates the thermogenic response and counteracts meetabolic disease. A disease-associated genetic variant of GPR3 in patient-derived adiposctes revealed that GPR3 acts as a regulator of human thermogenic adipose tissue (Sveidahl Johansen et al. 2021).

GPR3 of Homo sapiens


TC#NameOrganismal TypeExample

The Ocular albinism type 1 gene product, OA1, or G-protein coupled receptor 143 (GPR143) of 404 aas and 7 established TMSs (Sone and Orlow 2007).  OA1 (GPR143) is a pigment cell-specific intracellular glycoprotein that is mutated in patients with ocular albinism type 1, the most common form of ocular albinism. Its cellular localization appears to be endolysosomal and melanosomal.  It is a receptor for tyrosine, L-DOPA and dopamine. Binding of L-DOPA stimulates Ca2+ influx into the cytoplasm, increases secretion of the neurotrophic factor SERPINF1 and relocalizes beta arrestin at the plasma membrane; this ligand-dependent signaling occurs through a G(q)-mediated pathway in melanocytic cells. Its activity is mediated by G proteins which activate the phosphoinositide signaling pathway. It also plays a role as an intracellular G protein-coupled receptor involved in melanosome biogenesis, organization and transport (Palmisano et al. 2008; Giordano et al. 2009).


OA1 of Homo sapiens


TC#NameOrganismal TypeExample

The G-protein-coupled bile acid receptor of 330 aas and 7 TMSs, GPCR19. Bile acid-binding induces its internalization, activation of extracellular signal-regulated kinase and intracellular cAMP production. May be involved in the suppression of macrophage functions by bile acids (Maruyama et al. 2002; Kawamata et al. 2003; Häussinger and Kordes 2017).

GPCR19 of Homo sapiens


TC#NameOrganismal TypeExample

Putative G-protein receptor, GPCR, of 505 aas and 7 TMSs.

GPCR of Phytophthora sojae (Soybean stem and root rot agent) (Phytophthora megasperma f. sp. glycines)


Putative G-protein receptor of 600 aas and 7 TMSs, GPR107.

GPR107 of Homo sapiens


Uncharacterized protein, putative G-protein receptor of 421 aas and 7 TMSs.

UP of Entamoeba histolytica


TC#NameOrganismal TypeExample

Serpentine receptor, class alpha-6 (α6) of 329 aas and 7 TMSs, Sra-6.  Chemoreception is mediated in Caenorhabditis elegans by members of the seven-transmembrane G-protein-coupled receptor class (7TM GPCRs) of proteins which are of the serpentine type. Sra is part of the Sra superfamily of chemoreceptors. Chemoperception is one of the central senses of soil nematodes like C. elegans which are otherwise 'blind' and 'deaf'.

Sra of Caenorhabditis elegans


Serpentine Receptor, class AB (class A-like) of 331 aas and 7 TMSs.

SraR, class AB of Caenorhabditis elegans


Serpentine Receptor, class B (beta) of 350 aas and 7 TMSs.

Sra-B of Caenorhabditis elegans


Uncharacterized serpentine receptor of 336 aas and 7 TMSs. 

Receptor of Caenorhabditis elegans


Serpentine receptor class alpha/beta-14 of 280 aas and 7 TMSs.

SraA14 of Toxocara canis


Uncharacterized protein of 334 aas and 7 TMSs.

UP of Ancylostoma ceylanicum


Uncharacterized protein of 575 aas and 7 TMSs.

UP of Caenorhabditis elegans


Serpentine receptor class alpha-9, Sra-9, of 331 aas and 7 TMSs. It belongs to a chemosensory gene family, the serpentine receptor class ab (srab), which exists with 25 members in C. elegans and 14 members in C. briggsae (Chen et al. 2005). Sra-9 and Nlp-26 are required for polarized epidermal growth factor (EGF) secretion (Mereu et al. 2020).

Sra-9 of Caenorhabditis elegans


TC#NameOrganismal TypeExample

Serpentine receptor class r-10, Odr10, of 339 aas and 7 TMSs. It is an odorant receptor which affects chemotaxis to the volatile odorant diacetyl (Sengupta et al. 1996). It specifies AWA neuronal cell fate via the odr-7 pathway (Sagasti et al. 1999).

Odr10 of Caenorhabditis elegans


Chemoreceptor of 349 aas and 7 TMSs.

Chemoreceptor of Ancylostoma ceylanicum


G protein-coupled receptor of 463 aas and 7 TMSs.

GPCR of Pristionchus pacificus


Chemoreceptor of 386 aas and 7 TMSs.

Chemoreceptor of Ancylostoma duodenale


Uncharacterized protein of 547 aas and 7 TMSs.

UP of Diploscapter pachys


GPCR, serpentine receptor class j (Srj) family-containing protein of 333 aas and 7 TMSs.

GPCR of Strongyloides ratti


Str-19 of 344 aas and 7 TMSs.

Str-19 of Bursaphelenchus xylophilus (pine wood nematode)


TC#NameOrganismal TypeExample

Uncharacterized protein of 237 aas and 7 TMSs

UP of Candidatus Prometheoarchaeum syntrophicum


Uncharacterized protein of 239 aas and 7 TMSs.

UP of Candidatus Lokiarchaeota archaeon (sediment metagenome)


Uncharacterized protein of 247 aas and 7 TMSs.

UP of Candidatus Heimdallarchaeota archaeon (marine sediment metagenome)


TC#NameOrganismal TypeExample

Tyramine/octopamine receptor.  Inhibited by amitraz metabolites (Casida and Durkin 2013).


Tyramine/octopamine receptor of Schistosoma mansoni (G4VI72)


Dopamine receptor D2, DRD2, of 443 aas.  Residues involved in signaling have been identified (Kota et al. 2015).


DRD2 of Homo sapiens


β1-adrenergic receptor of 477 aas and 7 TMSs.  It can serve as an ATP-independent phospholipid flippase (scramblase) (Goren et al. 2014; Chauhan et al. 2016). Active-state structures of the β1-adrenoceptor (β1AR) bound to conformation-specific nanobodies in the presence of agonists of varying efficacy have been solved (Warne et al. 2019). Comparison with inactive-state structures of β1AR bound to the identical ligands showed a 24 to 42% reduction in the volume of the orthosteric binding site. Potential hydrogen bonds were also shorter, and there was up to a 30% increase in the number of atomic contacts between the receptor and ligand. This explains the increase in agonist affinity of GPCRs in the active state for a wide range of structurally distinct agonists (Warne et al. 2019).

β1-adrenergic receptor of Homo sapiens


Serotonin receptor, Cg5-HTR-1, of 382 aas. It mediates immune responses in the oyster (Jia et al. 2018).

Cg5-HTR-1 of Crassostrea gigas


The B96Bom octopamine receptor of 479 aas and 7 TMSs in a 5 + 2 TMS arrangement.  The N-terminus of B96Bom, is N-myristoylated and translocated across the membrane (Utsumi et al. 2005).

B96Bom receptor of Bombyx mori


5-hydroxytryptamine receptor 1A, 5HTR1a, of 422 aas and 7 TMSs.  G-protein coupled receptor for 5-hydroxytryptamine (serotonin) also functions as a receptor for various drugs and psychoactive substances (Harrington et al. 1994). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase (Gadgaard and Jensen 2020).

5HTR1a of Homo sapiens


5-hydroxytryptamine receptor-like protein of 540 aas and 7 TMSs in a 1 + 4 + 2 TMS arrangement.

Receptor of Biomphalaria glabrata


The α2A adrenergic receptor in Family A GPCR; of 465 aas and 7 TMSs (Hilger et al. 2020).

Alpha2 AR of Homo sapiens

G-protein coupled receptor for 5-hydroxytryptamine (serotonin), 5-HTR2A of 471 aas and 7 TMSs (Cussac et al. 2008, Knauer et al. 2009). It also functions as a receptor for various drugs and psychoactive substances, including mescaline, psilocybin, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and lysergic acid diethylamide (LSD) (Wacker et al. 2017). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors. Beta-arrestin family members inhibit signaling via G proteins and mediate activation of alternative signaling pathways. Signaling activates phospholipase C and a phosphatidylinositol-calcium second messenger system that modulates the activity of phosphatidylinositol 3-kinase and promotes the release of Ca2+ ions from intracellular stores. It affects neural activity, perception, cognition and mood (González-Maeso et al. 2008), and plays a role in the regulation of behavior, while acting as a receptor for human JC polyomavirus/JCPyV (Assetta et al. 2013). Additionally, 5-HT stimulates PLC/IP3 receptor signals via the 5-HT2A receptor, and the tmAC/PKA/CatSper channel signals via the 5-HT4 receptor. After sAC and PKA are activated by these stimulations, sperm hyperactivation is enhanced (Sakamoto et al. 2021).

5-HT2A receptor of Homo sapiens


5-Hydroxytryptamine (serotonin) receptor 4, HTR4, of 338 aas and 7 TMSs. This is one of the several different receptors for 5-hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. The activity of this receptor is mediated by G proteins that stimulate adenylate cyclase. The tmAC/PKA/CatSper channel signals via the 5-HT4 receptor, and after sAC and PKA are activated by such stimulation, sperm hyperactivation is enhanced (Sakamoto et al. 2021).


HTR4 of Homo sapiens


The muscarinic acetylcholine G-protein-coupled receptor (Jo et al., 2010). Endothelial-dependent muscarinic receptor signaling acts largely through TRPV4 sparklet-mediated stimulation of IK (1.A.1.16.2) and SK (1.A.1.16.1) channels to promote vasodilation. There are five muscarinic receptor subtypes (M1R to M5R), which, despite sharing a high degree of sequence identity in the transmembrane region, couple to different heterotrimeric G proteins to transmit signals. M1R, M3R, and M5R couple to the Gq/ 11 family, whereas M2R and M4R couple to the Gi/ o family. Maeda et al. 2019 presented and compared the cryo-electron microscopy structures of M1R in complex with G11 and M2R in complex with GoA. The M1R-G11 complex exhibits distinct features, including an extended transmembrane helix 5 and carboxyl-terminal receptor tail that interacts with the G protein. Detailed analysis provides a framework for understanding the molecular determinants of G-protein coupling selectivity (Maeda et al. 2019).


The muscarinic acetylcholine receptor (7TMSs; rhodopsin superfamily) of Mus musculus (P12657)


Tryamine receptor isoform A


Tyramine receptor of Drosophila melanogaster (E1JI27)


Adenosine receptor A1 of 326 aas and 7 TMSs. 


Adenosine receptor A1 of Homo sapiens (P30542)


β-2 adrenergic receptor, β2-AR. Activates adenylate cyclase through G proteins. Binds epinephrine with 30x greater affinity than norepenephrine.  Functions as an ATP-independent phospholipid flippase (scramblase) (Goren et al. 2014). A parameterized MARTINI program can be used to predict the hinging motions of the protein (Li et al. 2019). The drugs, salmeterol, formoterol and salbutamol, constitute the frontline treatment for asthma and other chronic pulmonary diseases. These drugs activate beta2-AR, and differ significantly in their clinical onset and durations of actions. Membrane lipids facilitate access and binding of the ligands, affecting their molecular recognition and pharmacology (Szlenk et al. 2021).  Fullerene and fullerene derivatives affect the local structure of beta2AR, especially the distortion of helix4, but bring about no great changes within the overall structure (Ren et al. 2022).



β-2-AR of Homo sapiens (P07550)


The serotonin or 5-hydroxytrytamine (5-HT) G protein-coupled receptor, 5HT1B.  Wang et al (2013) reported the crystal structures of the human 5-HT1B  bound to the agonist antimigraine medications ergotamine and dihydroergotamine. The structures revealed similar binding modes for these ligands, which occupy the orthosteric pocket and an extended binding pocket close to the extracellular loops. The orthosteric pocket is formed by residues conserved in the 5-HT receptor family.


5-HT1B of Homo sapiens


The serotonic or 5-hydroxytrytamine (5-HT) G protein-coupled receptor, 5HT2B. The structure of this receptor bound to ergotamine, the precursor of the hallucinogen, lysergic acid diethylamide, has been determined (Wacker et al., 2013). It reveals differences from those observed for 5-HT1B (9.B.14.3.6).



5-HT2B of Homo sapiens


Adenosine A2a receptor of 412 aas and 7 TMSs. It is a lipid flippase and a water channel (see below). The activity of this receptor is mediated by G proteins which activate adenylyl cyclase.  The crystal structure has been solved revealing a continuous water channel (Yuan et al. 2015).  Tryptophan-246 in TMS6 forms the gate. Conformational changes in TMSs 6 and 7 produce local changes in the lipid bilayer (Yuan et al. 2015).  The protein can function as an ATP-independent phopholipid flippase (scramblase) (Goren et al. 2014). Yuan et al. 2015 found that the conserved W246(6.48) residue in transmembrane helix TM6 performs a key rotamer toggle switch. Agonist binding induces the sidechain of W246(6.48) to fluctuate between two distinct conformations, enabling the diffusion of water molecules from the bulk into the center of the receptor. After passing the W246(6.48) gate, the internal water molecules induce another conserved residue, Y288(7.53), to switch to a distinct rotamer conformation establishing a continuous transmembrane water pathway. Further, structural changes of TM6 and TM7 induce local structural changes of the adjacent lipid bilayer (Yuan et al. 2015). The human A2A adenosine receptor was structurally determined by microcrystal electron diffraction (MicroED) after converting the lipidic cubic phase (LCP) into the sponge phase followed by focused ion-beam milling. Martynowycz et al. 2021 determined the structure of the A2A adenosine receptor to 2.8 Å resolution and resolved an antagonist in its orthosteric ligand-binding site, as well as four cholesterol molecules bound around the receptor. Fusion protein strategies for cryo-EM study of this and other G protein-coupled receptors have been described (Zhang et al. 2022).


Adenosine receptor A2a of Homo sapiens


The dopamine receptor D3, DRD3 or D3R of 400 aas.  Residues involved in receptor signaling have been identified (Kota et al. 2015), and several agonists are known (Xu et al. 2016). The atomic-level dopamine activation mechanism for transmitting extracellular ligand binding events through transmembrane helices to the cytoplasmic G protein has been elucidated (Weng et al. 2017). In agonist-bound systems, the D3R N-terminus forms a "lid-like" structure and lies flat on the binding site opening, whereas in antagonist-bound systems, the N-terminus exposes the binding cavity. A continuous water pathway is present only in the dopamine-Galphai-bound system. In the inactive D3Rs, water entry is hindered by the hydrophobic layers. It was proposed that upon agonist binding, the "lid-like" conformation of the N-terminus induces a series of molecular switches to increase the volume of the D3R cytoplasmic binding part for G protein association. Water enters the transmembrane region, inducing molecular switches to assist in opening the hydrophobic layers to form a continuous water channel, which is crucial for maintaining a fully active conformation for signal transduction (Weng et al. 2017). S-Deoxyephedrine can move through molecular channels within D3R (Li et al. 2017).


DRD3 of Homo sapiens


TC#NameOrganismal TypeExample

TC#NameOrganismal TypeExample

Calcitonin receptor 


Calcitonin receptor of Homo sapiens (P30988)


Secretin receptor


Secretin receptor of Homo sapiens (P47872)


Parathyroid hormone/parathyroid hormone-related peptide-1 receptor, PTH1R, of 573 aas and 8 or 9 TMSs in a 1 + 7 or 8 TMS arrangement. PTH1R is a class B G protein-coupled receptor central to calcium homeostasis and a therapeutic target for osteoporosis and hypoparathyroidism. Zhao et al. 2019 reported the cryo-EM structure of human PTH1R bound to a long-acting PTH analog and the stimulatory G protein. The bound peptide adopted an extended helix with its amino terminus inserted deeply into the receptor TMS, which led to partial unwinding of the carboxyl terminus of TMS6 and induceed a sharp kink at the middle of this helix to allow the receptor to couple with the G protein, while the extracellular domain adopted multiple conformations (Zhao et al. 2019).


Parathyroid hormone/parathyroid hormone-related peptide receptor of Homo sapiens (Q03431)


Calcitonin gene-related peptide type 1 receptor (CGRP type 1 receptor) (Calcitonin receptor-like receptor). It is involved in the regulation of vascular tone and the modulatioin of inflammatory and metabolic responses (Hendrikse et al. 2019). The high resoution 3-d structure is known, revealing its mechanism of receptor activation, including the conformational dynamics that occur upon agonist binding (Josephs et al. 2021).


CALCRL of Homo sapiens


Glucagon receptor of 477 aas and 7 TMSs (Family B GPCR; Hilger et al. 2020) (MacNeil et al. 1994).  It is the G-protein coupled receptor for glucagon that plays a central role in the regulation of blood glucose levels and glucose homeostasis (Zhou et al. 2009). It does so by regulating the rate of hepatic glucose production by promoting glycogen hydrolysis and gluconeogenesis, and it mediates the responses to fasting. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Promotes activation of adenylate cyclase and plays a role in signaling via a phosphatidylinositol-calcium second messenger system. The 3-D structure has been determined (Siu et al. 2013; Zhang et al. 2017).  In addition, its structure with glucagon and two distinct classes of heterotrimeric G-proteins, Gs and Gi1, has been determined (Qiao et al. 2020; Chang et al. 2020).

GCGR of Homo sapiens


PDF receptor


PDF receptor of Drosophila melanogaster (Q9W4Y2)


Corticotropin-releasing factor receptor-1, CRHR1. The structure is known (Hollenstein et al. 2013). Structural changes in CRFR1 upon antagonist binding and the role of single nucleotide polymorphisms have been investigated (Latek 2017). This G-protein coupled receptor for CRH (corticotropin-releasing factor) and UCN (urocortin) has high affinity for CRH and UCN. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and down-stream effectors such as adenylate cyclase. CRHR1 promotes the activation of adenylate cyclase, leading to increased intracellular cAMP levels. It inhibits the activity of the calcium channel CACNA1H (TC# 1.A.1.11.5) (Tao et al. 2008). Required for normal embryonic development of the adrenal gland and for normal hormonal responses to stress. Plays a role in the response to anxiogenic stimuli.


CRHR1 of Homo sapiens (P34998)


Diuretic hormone receptor


Diuretic hormone receptor of Acheta domesticus (Q16983)


Gastric inhibitory polypeptide receptor 


Gastric inhibitory polypeptide receptor of Homo Sapiens (P48546)


Glucagon-like peptide 1 receptor


Glucagon-like peptide 1 receptor of Homo sapiens (P43220)


Growth hormone-releasing hormone receptor


Growth hormone-releasing hormone receptor of Homo sapiens (Q02643)


Pituitary adenylate cyclase-activating polypeptide type 1 receptor


Pituitary adenylate cyclase-activating polypeptide type 1 receptor of Homo sapiens (P41586)


Vasoactive intestinal polypeptide receptor 1


Vasoactive intestinal polypeptide receptor 1 of Homo sapiens (P32241)


TC#NameOrganismal TypeExample

Cyclic AMP receptor 1


Cyclic AMP receptor 1 of Dictyostelium discoideum (P13773)


GCR1 of 326 aas and 7 TMSs. Together with GPA1, may regulate the cell cycle via a signaling cascade that uses phosphatidylinositol-specific phospholipase C (PI-PLC) as an effector and inositol 1,4,5-trisphosphate (IP3) as a second messenger. Mediates responses to blue light and abscisic acid (Warpeha et al. 2007).

GCR1 of Arabidopsis thaliana (Mouse-ear cress)


Putative cyclic AMP receptor of 428 aas and 7 TMSs (Kulkarni et al. 2005).

cAMP receptor of the plant pathogenic fungus, Magnaporthe grisea (Rice blast fungus) (Pyricularia oryzae)


TC#NameOrganismal TypeExample

EGF-like module-containing mucin-like hormone receptor-like 1


EGF-like module-containing mucin-like hormone receptor-like 1 of Homo sapiens (Q14246)


Adhesion G-protein coupled receptor G2, ADGRG2, of 1017 aas and 8 TMSs, one N-terminal and 7 C-terminal. It may be involved in a signal transduction pathway controlling epididymal function and male fertility as well as fluid exchange within the epididymis (Wu et al. 2020). β-arrestin-1 acts as a scaffold for ADGRG2/CFTR complex formation in apical membranes, whereas specific residues of ADGRG2 confer coupling specificity for different G protein subtypes, which is critical for male fertility (Zhang et al. 2018).

ADGRG2 of Homo sapiens


Full length G-protein coupled receptor 98 (GPR98) of 6306 aas and 7 C-terminal TMSs. It is also called the monogenic audiogenic seizure susceptibility protein 1 homologue, the usher syndrome type-2C protein, and the very large G-protein coupled receptor 1 (VLGR1).  It plays a role in CNS development and exists as multiple processed isoforms.



GPR98 of Homo sapiens


CD97 antigen or adhesion GPCR (ADGRE5), of 835 aas amd 7 C-terminal TMSs. They play a role in tumorigenesis (Aust et al. 2016). Maser and Calvet 2020 reviewed structural and functional features shared by polycystin-1 (TC# 1.A.5.1.1) and the adhesion GPCRs and discussed the implications of such similarities for our understanding of the functions of this complicated protein.


CD97 antigen of Homo sapiens (P48960)


EGF, latrophilin and seven transmembrane domain-containing protein 1


EGF, latrophilin and seven transmembrane domain-containing protein 1 of Homo sapiens (Q9HBW9)


Cadherin EGF LAG seven-pass G-type receptor 1, CELSR1 of 3014 aas and 7 TMSs near the C-terminus. Association of CELSR1 with Frizzled-6 in Drosophiila melanogaster (see TC# 9.A.14.16.1 for Frizzeled-1) is important, enabling efficient Frizzled-6 delivery to the cell surface, providing a quality-control mechanism that ensures appropriate stoichiometry of these two planar cell polarity (PCP) proteins at cell boundaries (Tang et al. 2020).



Cadherin EGF LAG seven-pass G-type receptor 1 of Homo sapiens (Q9NYQ6)


Latrophilin receptor (Lat-2)


Lat-2 of Caenorhabditis elegans (B2MZA8)


Brain-specific angiogenesis inhibitor 2


Brain-specific angiogenesis inhibitor 2 of Homo sapiens (O60241)


Adhesin G-protein-coupled receptor, BAI3 (ARGRB3) of 1522 aas.  It plays a role in the regulation of synaptogenesis and dendritic spine formation, at least partly via interaction with ELMO1 and RAC1. It promotes myoblast fusion through ELMO/DOCK1 (Hamoud et al. 2014). Complement 1q-like protein inhibits insulin secretion froms pancreatic β-cells via BAI3 (Gupta et al. 2018).

BAI3 of Homo sapiens (Human)


Adhesion 6 protein-coupled receptor, ADGRL3, or latrophilin-3, LPHN3, of 1447 aas and 7 central TMSs.  It plays a role in cell-cell adhesion and neuron guidance via its interactions with FLRT2 and FLRT3 that are expressed at the surface of adjacent cells (Lu et al. 2015). It also plays a role in the development of glutamatergic synapses in the cortex and determines the connectivity rates between the principal neurons in the cortex.  Knockout of latrophilin-3 in rats causes hyperactivity, hyper-reactivity, under-response to amphetamine, and disrupted dopamine markers (Regan et al. 2019).


ADGRL3 of Homo sapiens


LATROPHILIN-2, ADGRL2 or Adhesion G protein-coupled receptor L2, LEC1, LPHH1, LPHN2 of 1459 aas.  It is a calcium-independent receptor of low affinity for alpha-latrotoxin, an excitatory neurotoxin present in black widow spider venom which triggers massive exocytosis from neurons and neuroendocrine cells. This receptor has been implicated in the regulation of exocytosis (Moreno-Salinas et al. 2019; Burbach and Meijer 2019).

ADGRL2 of Homo sapiens


TC#NameOrganismal TypeExample

Metabotropic glutamate receptor 1, class C.  The parallel 7 TMS dimer is mediated by cholesterol, which suggests that signaling initiated by glutamate's interaction with the extracellular domain might be mediated via 7 TMS interactions within the full-length receptor dimer (Wu et al. 2014). This protein appears to be involved in regulation of  the functions of glycine receptors (see TC# 1.A.9.3.1) (Zhang et al. 2019).


Metabotropic glutamate receptor 1 of Homo sapiens (Q13255)


Taste receptor TAS1R3, T1R3, TR3 of 852 aas and 7 C-terminal TMSs. TAS1R1/TAS1R3 responds to the umami (amino acid) taste stimuli (the taste of monosodium glutamate) (Li et al. 2002). TAS1R2/TAS1R3 recognizes diverse natural and synthetic sweeteners (Li et al. 2002), and this heterodimer as well as TAS1R1/TAS1R3 confers sweet-sensing abilities to songbirds (nearly half of all birds) (Toda et al. 2021). TAS1R3 is essential for the recognition and response to the disaccharide trehalose (Ariyasu et al. 2018). Sequence differences within and between species can significantly influence the selectivity and specificity of taste responses. This receptor may function in a parallel sweet-sensitive pathway, involving signaling mechanisms, neural processing, interactions with endocrine hormonal mechanisms, and sensitivity to different stimuli, and its physiological role in detecting the energy content of food in preparation for digestion (von Molitor et al. 2020).

TAS1R3 of Homo sapiens


Extracellular calcium-sensing receptor of 1078 aas and 7 TMSs, CASR, GPCRC2A, PCAR1.  It senses changes in the extracellular concentration of calcium ions and plays a key role in maintaining calcium homeostasis (Kim et al. 2016). In the inner ear membranous labyrinth, CaSR localizes exclusively tp mitochondrion-rich cell, suggesting a unique role of the endolymphatic sac epithelium in CaSR-mediated sensing and control(Bächinger et al. 2019).



Extracellular calcium-sensing receptor of Homo sapiens (P41180)


G-protein coupled receptor family C group 6 member A


G-protein coupled receptor family C group 6 member A of Homo sapiens (Q5T6X5)


Taste receptor type 1 member 2, TAS1R2, GPR71, TR2, of 839 aas and 7 C-terminal TMSs. Sweet substances are detected by taste-bud cells upon binding to the sweet-taste receptor, a T1R2/T1R3 heterodimeric G protein-coupled receptor (von Molitor et al. 2020).


Taste receptor type 1 member 2 of Homo sapiens (Q8TE23)


Taste receptor type 1 member 1, TAS1


TAS1 of Homo spaiens


Vomeronasal type-2 receptor 1, Vmn2r1, of 912 aas and 7 C-terminal TMSs.

Vmn2r1 of Mus musculus


G-protein coupled receptor family C group 6 member A, Gprc6a, of 877 aas and 7 C-terminal TMSs. It is an olfactory receptor that is activated by amino acids that act as potent odorants in fish. It is most highly activated by basic amino acids such as L-lysine and L-arginine (Speca et al. 1999).

Gprc6a of Carassius auratus (Goldfish)


Metabotropic glutamate receptor 5, mGluR5, GRM5, of 1212 aas and 7 TMSs. It is a G-protein-coupled receptor for glutamate. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors. Signaling activates a phosphatidylinositol-calcium second messenger system and generates a calcium-activated chloride current. GRM5 plays a role in the regulation of synaptic plasticity and the modulation of the neural network activity (Minakami et al. 1994). The structure of the transmembrane domain has been determined (Doré et al. 2014). The prevalence, presentation, and progression of Alzheimer's disease (AD) differ between men and women, although β-amyloid (Aβ) deposition is a pathological hallmark of AD in both sexes. Aβ-induced activation of the neuronal glutamate receptor mGluR5 is linked to AD progression. However, mGluR5 exhibits distinct sex-dependent profiles (Abd-Elrahman et al. 2020). mGluR5 isolated from male mouse cortical and hippocampal tissues bound with high affinity to Aβ oligomers, whereas mGluR5 from female mice exhibited no such affinity. This sex-selective Aβ-mGluR5 interaction is not depend on estrogen, but rather Aβ interaction with cellular prion protein (PrPC), which was detected only in male mouse brain homogenates. The ternary complex between mGluR5, Aβ oligomers, and PrPC was essential to elicit mGluR5-dependent pathological suppression of autophagy in primary neuronal cultures. Pharmacological inhibition of mGluR5 reactivated autophagy, mitigated Aβ pathology, and reversed cognitive decline in male APPswe/PS1ΔE9 mice, but not in their female counterparts. Aβ oligomers also bound with high affinity to human mGluR5 isolated from postmortem donor male cortical brain tissue, but not that from female samples, suggesting that this mechanism may be relevant to patients. mGluR5 does not contribute to Aβ pathology in females, highlighting the complexity of mGluR5 pharmacology and Aβ signaling that supports the need for sex-specific stratification in clinical trials assessing AD therapeutics (Abd-Elrahman et al. 2020).

GRM5 of Homo sapiens


Glutamate metabolomic receptor 2, Grm2, of 872 aas with 1 N-terminal and 7 C-terminal TMSs. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling inhibits adenylate cyclase activity (Flor et al. 1995). It may mediate suppression of neurotransmission or may be involved in synaptogenesis or synaptic stabilization. It forms a complex with the serotonin receptor (González-Maeso et al. 2008) as well as with SNAT6, the glutamate/glutamine transporter (Gandasi et al. 2021).

Grm2 of Homo sapiens


TC#NameOrganismal TypeExample

Olfactory receptor 1E1


Olfactory receptor 1E1 of Homo sapiens (P30953)


Olfactory receptor, OR2AG1 of 316 aas and 7 TMSs (Song et al. 2009).


Olfactory receptor, OR2AG1 of Homo sapiens


Olfactory receptor OR51E2 of 320 aas and 7 TMSs. This olfactory receptor (Jovancevic et al. 2017) is activated by the odorant, beta-ionone, a synthetic terpenoid (Neuhaus et al. 2009). Its activity is propably mediated by G-proteins leading to the elevation of intracellular Ca2+, cAMP and activation of the protein kinases PKA and MAPK3/MAPK1 (Gelis et al. 2016). Stimulation of OR51E2 by beta-ionone affects melanocyte proliferation, differentiation, and melanogenesis and increases proliferation and migration of primary retinal pigment epithelial  cells (Jovancevic et al. 2017). Activation by the short-chain fatty acids (SCFA), acetate,  L-lactate and propionate, may positively regulate renin secretion and increase blood pressure (Pluznick et al. 2013). It may also be activated by steroid hormones and regulate cell proliferation (Neuhaus et al. 2009). The orthologues from bovine species are ~ 92% identical to the human ortholog, and there appears to be an expansion in the gene copt number of olfactory receptors (Low et al. 2022).

OR51E2 of Homo sapiens


TC#NameOrganismal TypeExample

Prostaglandin E2 receptor EP1 subtype


Prostaglandin E2 receptor EP1 subtype of Homo sapiens (P34995)