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Trace amine receptor in GtoPdb v.2025.3
Full text linkTrace amine-associated receptors were discovered from a search for novel 5-HT receptors [9], where 15 mammalian orthologues were identified and divided into two families. The TA1 receptor (nomenclature as agreed by the NC-IUPHAR Subcommittee for the Trace amine receptor [59]) has affinity for the endogenous trace amines tyramine, β-phenylethylamine and octopamine in addition to the classical amine dopamine [9]. Emerging evidence suggests that TA1 is a modulator of monoaminergic activity in the brain [95] with TA1 and dopamine D2 receptors shown to form constitutive heterodimers when co-expressed [30]. In addition to trace amines, receptors can be activated by amphetamine-like psychostimulants, and endogenous thyronamines
Vasopressin and oxytocin receptors in GtoPdb v.2025.3
Full text linkVasopressin (AVP) and oxytocin (OT) receptors (nomenclature as recommended by NC-IUPHAR [98]) are activated by the endogenous cyclic nonapeptides vasopressin and oxytocin. These peptides are derived from precursors which also produce neurophysins (neurophysin I for oxytocin; neurophysin II for vasopressin). Vasopressin and oxytocin differ at only 2 amino acids (positions 3 and 8). There are metabolites of these neuropeptides that may be biologically active [71]
Ionotropic glutamate receptors in GtoPdb v.2025.3
Full text linkThe ionotropic glutamate receptors comprise members of the NMDA (N-methyl-D-aspartate), AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid) and kainate receptor classes, named originally according to their preferred, synthetic, agonist [60, 99, 163]. Receptor heterogeneity within each class arises from the homo-oligomeric, or hetero-oligomeric, assembly of distinct subunits into cation-selective tetramers. Each subunit of the tetrameric complex comprises an extracellular amino terminal domain (ATD), an extracellular ligand binding domain (LBD), 3 TM domains (M1, M3 and M4), a channel lining re-entrant \u27p-loop\u27 (M2) located between M1 and M3 and an intracellular carboxy- terminal domain (CTD) [106, 74, 115, 163, 88]. The X-ray structure of a homomeric ionotropic glutamate receptor (GluA2- see below) has recently been solved at 3.6Å resolution [151] and although providing the most complete structural information current available may not representative of the subunit arrangement of, for example, the heteromeric NMDA receptors [77]. It is beyond the scope of this supplement to discuss the pharmacology of individual ionotropic glutamate receptor isoforms in detail; such information can be gleaned from [60, 72, 34, 83, 44, 122, 27, 71, 163, 120, 121, 171]. Agents that discriminate between subunit isoforms are, where appropriate, noted in the tables and additional compounds that distinguish between receptor isoforms are indicated in the text below.The classification of glutamate receptor subunits has been re-addressed by NC-IUPHAR [31]. The scheme developed recommends a nomenclature for ionotropic glutamate receptor subunits that is adopted here.NMDA receptorsNMDA receptors assemble as obligate heteromers that may be drawn from GluN1, GluN2A, GluN2B, GluN2C, GluN2D, GluN3A and GluN3B subunits. Alternative splicing can generate eight isoforms of GluN1 with differing pharmacological properties. Various splice variants of GluN2B, 2C, 2D and GluN3A have also been reported. Activation of NMDA receptors containing GluN1 and GluN2 subunits requires the binding of two agonists, glutamate to the S1 and S2 regions of the GluN2 subunit and glycine to S1 and S2 regions of the GluN1 subunit [43, 28]. The minimal requirement for efficient functional expression of NMDA receptors in vitro is a di-heteromeric assembly of GluN1 and at least one GluN2 subunit variant, as a dimer of heterodimers arrangement in the extracellular domain [50, 106, 77]. However, more complex tri-heteromeric assemblies, incorporating multiple subtypes of GluN2 subunit, or GluN3 subunits, can be generated in vitro and occur in vivo. The NMDA receptor channel commonly has a high relative permeability to Ca2+ and is blocked, in a voltage-dependent manner, by Mg2+ such that at resting potentials the response is substantially inhibited.AMPA and Kainate receptorsAMPA receptors assemble as homomers, or heteromers, that may be drawn from GluA1, GluA2, GluA3 and GluA4 subunits. Transmembrane AMPA receptor regulatory proteins (TARPs) of class I (i.e. γ2, γ3, γ4 and γ8) act, with variable stoichiometry, as auxiliary subunits to AMPA receptors and influence their trafficking, single channel conductance gating and pharmacology (reviewed in [45, 110, 161, 70]). Functional kainate receptors can be expressed as homomers of GluK1, GluK2 or GluK3 subunits. GluK1-3 subunits are also capable of assembling into heterotetramers (e.g. GluK1/K2; [94, 127, 126]). Two additional kainate receptor subunits, GluK4 and GluK5, when expressed individually, form high affinity binding sites for kainate, but lack function, but can form heteromers when expressed with GluK1-3 subunits (e.g. GluK2/K5; reviewed in [127, 71, 126]). Kainate receptors may also exhibit \u27metabotropic\u27 functions [94, 139]. As found for AMPA receptors, kainate receptors are modulated by auxiliary subunits (Neto proteins, [126, 95]). An important function difference between AMPA and kainate receptors is that the latter require extracellular Na+ and Cl- for their activation [13, 128]. RNA encoding the GluA2 subunit undergoes extensive RNA editing in which the codon encoding a p-loop glutamine residue (Q) is converted to one encoding arginine (R). This Q/R site strongly influences the biophysical properties of the receptor. Recombinant AMPA receptors lacking RNA edited GluA2 subunits are: (1) permeable to Ca2+; (2) blocked by intracellular polyamines at depolarized potentials causing inward rectification (the latter being reduced by TARPs); (3) blocked by extracellular argiotoxin and joro spider toxins and (4) demonstrate higher channel conductances than receptors containing the edited form of GluA2 [147, 69]. GluK1 and GluK2, but not other kainate receptor subunits, are similarly edited and broadly similar functional characteristics apply to kainate receptors lacking either an RNA edited GluK1, or GluK2, subunit [94, 126]. Native AMPA and kainate receptors displaying differential channel conductances, Ca2+ permeabilites and sensitivity to block by intracellular polyamines have been identified [33, 69, 98]. GluA1-4 can exist as two variants generated by alternative splicing (termed ‘flip’ and ‘flop’) that differ in their desensitization kinetics and their desensitization in the presence of cyclothiazide which stabilises the nondesensitized state. TARPs also stabilise the non-desensitized conformation of AMPA receptors and facilitate the action of cyclothiazide [110]. Splice variants of GluK1-3 also exist which affects their trafficking [94, 126]
1I. Vitamin D receptor-like receptors in GtoPdb v.2025.3
Full text linkVitamin D (VDR), Pregnane X (PXR) and Constitutive Androstane (CAR) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [51, 1]) are members of the NR1I family of nuclear receptors, which form heterodimers with members of the retinoid X receptor family. PXR and CAR are activated by a range of exogenous compounds, with no established endogenous physiological agonists, although high concentrations of bile acids and bile pigments activate PXR and CAR [51]
Aquaporins in GtoPdb v.2025.3
No full textAquaporins and aquaglyceroporins are membrane channels that allow the permeation of water and certain other small solutes across the cell membrane, or in the case of AQP6, AQP11 and AQP12A, intracellular membranes, such as vesicles and the endoplasmic reticulum membrane [16]. Since the isolation and cloning of the first aquaporin (AQP1) [20], 12 additional mammalian members of the family have been identified, although little is known about the functional properties of one of these (AQP12A; Q8IXF9) and it is thus not tabulated. The other 12 aquaporins can be broadly divided into three families: orthodox aquaporins (AQP0,-1,-2,-4,-5, -6 and -8) permeable mainly to water, but for some additional solutes [4]; aquaglyceroporins (AQP3,-7 -9 and -10), additionally permeable to glycerol and for some isoforms urea [14], and superaquaporins (AQP11 and 12) located within cells [12]. Some aquaporins also conduct ammonia and/or H2O2 giving rise to the terms \u27ammoniaporins\u27 (\u27aquaammoniaporins\u27) and \u27peroxiporins\u27, respectively. Aquaporins are impermeable to protons and other inorganic and organic cations, with the possible exception of AQP1, although this is controversial [14]. One or more members of this family of proteins have been found to be expressed in almost all tissues of the body [reviewed in Yang (2017) [27]]. AQPs are involved in numerous processes that include systemic water homeostasis, adipocyte metabolism, brain oedema, cell migration and fluid secretion by epithelia. Loss of function mutations of some human AQPs, or their disruption by autoantibodies further underscore their importance [reviewed by Verkman et al. (2014) [24], Kitchen et al. (2105) [14]]. Functional AQPs exist as homotetramers that are the water conducting units wherein individual AQP subunits (each a protomer) have six TM helices and two half helices that constitute a seventh \u27pseudotransmembrane domain\u27 that surrounds a narrow water conducting channel [16]. In addition to the four pores contributed by the protomers, an additional hydrophobic pore exists within the center of the complex [16] that may mediate the transport through AQP1. Although numerous small molecule inhibitors of aquaporins, particularly APQ1, have been reported primarily from Xenopus oocyte swelling assays, the activity of most has subsequently been disputed upon retesting using assays of water transport that are less prone to various artifacts [5] and they are therefore excluded from the tables [see Tradtrantip et al. (2017) [23] for a review]
SLC28 and SLC29 families of nucleoside transporters in GtoPdb v.2025.3
Full text linkNucleoside transporters are divided into two families, the sodium-dependent, concentrative solute carrier family 28 (SLC28) and the equilibrative, solute carrier family 29 (SLC29). The endogenous substrates are typically nucleosides, although some family members can also transport nucleobases and organic cations [1]
Succinate receptor in GtoPdb v.2025.3
Full text linkNomenclature as recommended by NC-IUPHAR [8]. The succinate receptor (GPR91, SUCNR1) is activated by the tricarboxylic acid (or Krebs) cycle intermediate succinate and other dicarboxylic acids with less clear physiological relevance such as maleate [17]. Since its pairing with its endogenous ligand in 2004, intense research has focused on the receptor-ligand pair role in various (patho)physiological processes such as regulation of renin production [17, 40], ischemia injury [17], fibrosis [26], retinal angiogenesis [35], inflammation [26, 24], immune response [33], obesity [45, 27, 21], diabetes [43, 22, 40], platelet aggregation [39, 37] or cancer [29, 47]. The succinate receptor is coupled to Gi/o [11, 17] and Gq/11 protein families [32, 17, 41], whilst coupling to these G proteins is dependent on the cellular, metabolic and spatial context [23, 41]. Although the receptor is, upon ligand addition, rapidly desensitized [19, 32], and in some cells internalized [17], it seems to recruit arrestins weakly [10]. The cellular activation of the succinate receptor triggers various signalling pathways such as decrease of cAMP levels, [Ca2+]i mobilization and activation of kinases (ERK, c-Jun, Akt, Src, p38, PI3Kβ, etc.) [12]. The receptor is broadly expressed but is notably abundant in immune cells (M2 macrophages [41, 21], monocytes [33], immature dendritic cells [33], adipocytes [45], platelets [39, 37], etc.) and in the kidney [17]
Type XX RTKs: STYK1 in GtoPdb v.2025.3
Full text linkSimilar to the LMR RTK family, STYK1 has a truncated extracellular domain, but also displays a relatively short intracellular tail beyond the split kinase domain. Also known as NOK, STYK1 has been linked to EGFR signalling [2, 3]
Cyclic nucleotide-regulated channels (CNG) in GtoPdb v.2025.4
Full text linkCyclic nucleotide-gated (CNG) channels are responsible for signalling in the primary sensory cells of the vertebrate visual and olfactory systems. CNG channels are voltage-independent cation channels formed as tetramers. Each subunit has 6TM, with the pore-forming domain between TM5 and TM6. CNG channels were first found in rod photoreceptors [83, 120], where light signals through rhodopsin and transducin to stimulate phosphodiesterase and reduce intracellular cyclic GMP level. This results in a closure of CNG channels and a reduced ‘dark current’. Similar channels were found in the cilia of olfactory neurons [181] and the pineal gland [71]. The cyclic nucleotides bind to a domain in the C terminus of the subunit protein: other channels directly binding cyclic nucleotides include hyperpolarisation-activated, cyclic nucleotide-gated channels (HCN), ether-a-go-go and certain plant potassium channels.The HCN channels are cation channels that are activated by hyperpolarisation at voltages negative to ~-50 mV. The cyclic nucleotides cyclic AMP and cyclic GMP directly bind to the cyclic nucleotide-binding domain of HCN channels and shift their activation curves to more positive voltages, thereby enhancing channel activity. HCN channels underlie pacemaker currents found in many excitable cells including cardiac cells and neurons [65, 192]. In native cells, these currents have a variety of names, such as Ih, Iq and If. The four known HCN channels have six transmembrane domains and form tetramers. It is believed that the channels can form heteromers with each other, as has been shown for HCN1 and HCN4 [2]. High resolution structural studies of CNG and HCN channels has provided insight into the gating processes of these channels [139, 146, 140]. A standardised nomenclature for CNG and HCN channels has been proposed by the NC-IUPHAR Subcommittee on voltage-gated ion channels [108]
Acid-sensing (proton-gated) ion channels (ASICs) in GtoPdb v.2025.4
Full text linkAcid-sensing ion channels (ASICs, nomenclature as agreed by NC-IUPHAR [52, 2, 3]) are members of a Na+ channel superfamily that includes the epithelial Na+ channel (ENaC), the FMRF-amide activated channel (FaNaC) of invertebrates, the degenerins (DEG) of Caenorhabditis elegans, channels in Drosophila melanogaster and the mammalian bile acid-activated ion channel BASIC [94], previously known as BLINaC [75] and INaC [77]. ASIC subunits contain 2 TM domains and a large extracellular part whose shape resembles that of a hand, as shown by high-resolution structures of chicken and human ASIC1a [49, 43, 7, 101, 100, 81]. They assemble as homo- or heterotrimers to form proton-gated, voltage-insensitive, Na+ permeable, channels that are activated by levels of acidosis occurring in both physiological and pathophysiological conditions with ASIC3 also playing a role in mechanosensation (reviewed in [48, 93, 52, 74, 23]). Splice variants of ASIC1 [termed ASIC1a (ASIC, ASICα, BNaC2α) [88], ASIC1b (ASICβ, BNaC2β) [19] and ASIC1b2 (ASICβ2) [83]; note that ASIC1a is also permeable to Ca2+], ASIC2 [termed ASIC2a (MDEG1, BNaC1α, BNC1α) [70, 89, 42] and ASIC2b (MDEG2, BNaC1β) [60]] differ in the first third of the protein. Unlike ASIC2a (listed in table), heterologous expression of ASIC2b alone does not support H+-gated currents. A third member, ASIC3 (DRASIC, TNaC1) [87] is one of the most pH-sensitive isoforms (along with ASIC1a) and has the fastest activation and desensitisation kinetics, however can also carry small sustained currents. ASIC4 (SPASIC) evolved as a proton-sensitive channel but seems to have lost this function in mammals [62]. Mammalian ASIC4 does not support a proton-gated channel in heterologous expression systems but is reported to downregulate the expression of ASIC1a and ASIC3 [1, 47, 35, 58, 24]. ASICs channels are primarily expressed in central (ASIC1a, -2a, 2b and -4) and peripheral neurons including nociceptors (ASIC1-3) where they participate in neuronal sensitivity to acidosis. Humans express, in contrast to rodents, ASIC3 also in the brain [28]. ASICs have also been detected in photoreceptors and retinal cells (ASIC1-3), cochlear hair cells (ASIC1b), testis (hASIC3), pituitary gland (ASIC4), lung epithelial cells (ASIC1a and -3), urothelial cells, adipose cells (ASIC3), vascular smooth muscle cells (ASIC1-3), immune cells (ASIC1,-3 and -4) and bone (ASIC1-3) (ASIC distribution is reviewed in [59, 29, 46]). A neurotransmitter-like function of protons has been suggested, involving postsynaptically located ASICs of the CNS in functions such as learning and fear perception [36, 54, 104] and of the PNS in mechanoreceptor-neurite transmission [98, 97]. ASIC activation also contributes to cell damage in focal ischemia [95, 73] and autoimmune inflammation (arthritis and multiple sclerosis) [41, 96], as well as neuron activation during seizures and pain [93, 30, 31, 13, 33]. Heterologously expressed heteromultimers form ion channels with differences in kinetics, ion selectivity, pH- sensitivity and sensitivity to blockers that resemble some of the native proton activated currents recorded from neurones [60, 5, 39, 11]. In general, the known small molecule inhibitors of ASICs are non-selective or partially selective, whereas the venom peptide inhibitors have substantially higher selectivity and potency. Several clinically used drugs are known to inhibit ASICs, however they are generally more potent at other targets (e.g. amiloride at ENaCs, ibuprofen at COX enzymes) [72, 67]. The information in the tables below are for the effects of inhibitors on homomeric channels, for information of known effects on heteromeric channels see the comments below