IUPHAR/BPS Guide to Pharmacology CITE
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Other non-GPCR 7TM proteins in GtoPdb v.2025.2
Full text linkThese proteins are predicted to have 7TM domains, but functional studies have yet to confirm them as G protein-coupled receptors
Orai channels in GtoPdb v.2025.4
Full text linkOrai channels are pore forming proteins which underlie calcium release-activated calcium (CRAC) channels. In numerous cell types, calcium influx is predominantly governed by store-operated calcium channels (SOCs). The process of store-operated calcium entry (SOCE) is orchestrated through the concerted interaction of two essential molecular components: the pore-forming Orai proteins (Orai1-3) and the endoplasmic reticulum calcium-sensing stromal interaction molecules (STIM1 and STIM2) [25]
Corticotropin-releasing factor receptors in GtoPdb v.2025.3
Full text linkCorticotropin-releasing factor (CRF, nomenclature as agreed by the NC-IUPHAR subcommittee on Corticotropin-releasing Factor Receptors [35]) receptors are activated by the endogenous peptides corticotrophin-releasing hormone, a 41 amino-acid peptide, urocortin 1, 40 amino-acids, urocortin 2, 38 amino-acids and urocortin 3, 38 amino-acids. CRF1 and CRF2 receptors are activated non-selectively by CRH and UCN. CRF2 receptors are selectively activated by UCN2 and UCN3. Binding to CRF receptors can be conducted using radioligands [125I]Tyr0-CRF or [125I]Tyr0-sauvagine with Kd values of 0.1-0.4 nM. CRF1 and CRF2 receptors are non-selectively antagonized by α-helical CRF, D-Phe-CRF-(12-41) and astressin. CRF1 receptors are selectively antagonized by small molecules NBI27914, R121919, antalarmin, CP 154,526, CP 376,395. CRF2 receptors are selectively antagonized by antisauvagine and astressin 2B. Although selective small molecule CRF1 receptor antagonists were not effective in treating major depressive disorder, posttraumatic stress disorder, or alcohol use disorder in clinical trials, recent phase 2 studies have found that CRF1 receptor antagonists effectively reduce adrenocortical androgens and precursors in congentical adrenal hyperplasia [61]
Neuropeptide S receptor in GtoPdb v.2025.3
Full text linkThe neuropeptide S receptor (NPS receptor) responds to the 20 amino-acid peptide neuropeptide S derived from a precursor (NPS, P0C0P6). NPS activates its receptor at low nanomolar concentrations elevating intracellular cAMP and calcium levels [74]. Currently, some peptidic and small molecule NPS receptor antagonists are available as research tools [30, 82, 9, 62]. No NPS receptor ligands are currently used clinically
P2Y receptors in GtoPdb v.2025.3
Full text linkP2Y receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on P2Y Receptors [2, 4, 192]) are activated by the endogenous ligands ATP, ADP, UTP, UDP, and UDP-sugars. The eight mammalian P2Y receptors are activated by distinct nucleotides: P2Y1, P2Y11, P2Y12 and P2Y13 are activated by adenosine-nucleotides; P2Y2, P2Y4 can be activated by both adenosine and uridine nucleotides, with some species-specific differences; P2Y6 is mainly activated by UDP; P2Y14 is preferentially activated by sugar-uracil nucleotides. The missing numbers in the receptor nomenclature refer either to non-mammalian orthologs or receptors having some sequence homology to P2Y receptors but for which there is no functional evidence of responsiveness to nucleotides [390]. Based on their G protein coupling P2Y receptors can be divided into two subfamilies: P2Y1, P2Y2, P2Y4, P2Y6 and P2Y11 receptors couple via Gq proteins to stimulate phospholipase C followed by increases in inositol phosphates and mobilization of Ca2+ from intracellular stores. P2Y11 receptors couple in addition to Gs proteins followed by increased adenylate cyclase activity. In contrast, P2Y12, P2Y13, and P2Y14 receptors signal primarily through activation of Gi proteins and inhibition of adenylate cyclase activity or control of ion channel activity [390]. Clinically used drugs acting on these receptors include the dinucleoside polyphosphate diquafosol, agonist of the P2Y2 receptor subtype, approved in Japan and South Korea for the management of dry eye disease [243], and the P2Y12 receptor antagonists clopidogrel, prasugrel, cangrelor and ticagrelor, all approved as antiplatelet drugs [53, 326]
Relaxin family peptide receptors in GtoPdb v.2025.3
Full text linkRelaxin family peptide receptors (RXFP, nomenclature as agreed by the NC-IUPHAR Subcommittee on Relaxin family peptide receptors [23, 125]) may be divided into two pairs, RXFP1/2 and RXFP3/4. Endogenous agonists at these receptors are heterodimeric peptide hormones structurally related to insulin: relaxin-1, relaxin, relaxin-3 (also known as INSL7), insulin-like peptide 3 (INSL3) and INSL5. Species homologues of relaxin have distinct pharmacology and relaxin interacts with RXFP1, RXFP2 and RXFP3, whereas mouse and rat relaxin selectively bind to and activate RXFP1 [268]. relaxin-3 is the ligand for RXFP3 but it also binds to RXFP1 and RXFP4 and has differential affinity for RXFP2 between species [267]. INSL5 is the ligand for RXFP4 but is a weak antagonist of RXFP3. relaxin and INSL3 have multiple complex binding interactions with RXFP1 [275] and RXFP2 [138], which together with the N-terminal linker and LDLa module drive receptor activation by an unknown mechanism [270, 89]. INSL5 and relaxin-3 interact with their receptors using distinct residues in their B-chains for binding, and activation, respectively [55, 329, 158, 56]
Nicotinic acetylcholine receptors (nACh) in GtoPdb v.2025.3
Full text linkNicotinic acetylcholine (ACh) receptors are members of the Cys-loop family of transmitter-gated ion channels that includes the GABAA, strychnine-sensitive glycine and 5-HT3 receptors [217, 3, 161, 227, 261]. All nicotinic receptors are pentamers in which each of the five subunits contains 4 TM domains. Genes encoding a total of 17 subunits (α1-10, β1-4, γ, δ and ε) have been identified [122]. All subunits with the exception of α8 (present in avian species) have been identified in mammals. All α subunits possess two tandem cysteine residues near to the site involved in acetylcholine binding, and subunits not named α lack these residues [161]. The orthosteric ligand binding site is formed by residues within at least three peptide domains on the α subunit (principal component), and three on the adjacent subunit (complementary component). Nicotinic ACh receptors contain several allosteric modulatory sites. One such site, for positive allosteric modulators (PAMs) and allosteric agonists, has been proposed to reside within an intrasubunit cavity between the 4 TM domains [266, 89]; see also [108]). The high resolution crystal structure of the molluscan ACh binding protein, a structural homologue of the extracellular binding domain of a nicotinic receptor pentamer, in complex with several nicotinic receptor ligands (e.g.[35]) and the crystal structure of the extracellular domain of the α1 subunit bound to α-bungarotoxin at 1.94Â resolution [55], has revealed the orthosteric binding site in detail (reviewed in [217, 122, 39, 200]). Nicotinic receptors at the somatic neuromuscular junction of adult animals have the stoichiometry (α1)2β1δε, whereas an extrajunctional (α1)2β1γδ receptor predominates in embryonic and denervated skeletal muscle and other pathological states. Other nicotinic receptors are assembled as combinations of α(2-6) and β(2-4) subunits. For α2, α3, α4 and β2 and β4 subunits, pairwise combinations of α and β (e.g. α3β4 and α4β2) are sufficient to form a functional receptor in vitro, but far more complex isoforms may exist in vivo (reviewed in [98, 95, 161]). There is strong evidence that the pairwise assembly of some α and β subunits can occur with variable stoichiometry [e.g. (α4)2(β2)2 or (α4)3(β2)2] which influences the biophysical and pharmacological properties of the receptor [161]. α5 and β3 subunits lack function when expressed alone, or pairwise, but participate in the formation of functional hetero-oligomeric receptors when expressed as a third subunit with another α and β pair [e.g. α4α5αβ2, α4αβ2β3, α5α6β2, see [161] for further examples]. The α6 subunit can form a functional receptor when co-expressed with β4 in vitro, but more efficient expression ensues from incorporation of a third partner, such as β3 [265]. The α7, α8, and α9 subunits form functional homo-oligomers, but can also combine with a second subunit to constitute a hetero-oligomeric assembly (e.g. α7β2 and α9α10). For functional expression of the α10 subunit, co-assembly with α9 is necessary. The latter, along with the α10 subunit, appears to be largely confined to cochlear and vestibular hair cells. Comprehensive listings of nicotinic receptor subunit combinations identified from recombinant expression systems, or in vivo, are given in [161]. In addition, numerous proteins interact with nicotinic ACh receptors modifying their assembly, trafficking to and from the cell surface, and activation by ACh (reviewed by [160, 9, 120]).The nicotinic receptor Subcommittee of NC-IUPHAR has recommended a nomenclature and classification scheme for nicotinic acetylcholine (nACh) receptors based on the subunit composition of known, naturally- and/or heterologously-expressed nACh receptor subtypes [145]. Headings for this table reflect abbreviations designating nACh receptor subtypes based on the predominant α subunit contained in that receptor subtype. An asterisk following the indicated α subunit denotes that other subunits are known to, or may, assemble with the indicated α subunit to form the designated nACh receptor subtype(s). Where subunit stoichiometries within a specific nACh receptor subtype are known, numbers of a particular subunit larger than 1 are indicated by a subscript following the subunit (enclosed in parentheses- see also [46])
Adenylyl cyclases (ACs) in GtoPdb v.2025.3
Full text linkAdenylyl cyclase, E.C. 4.6.1.1, converts ATP to cyclic AMP and pyrophosphate. Mammalian membrane-delimited adenylyl cyclases (nomenclature as approved by the NC-IUPHAR Subcommittee on Adenylyl cyclases [11]) are typically made up of two clusters of six TM domains separating two intracellular, overlapping catalytic domains that are the target for the nonselective activators Gαs (the stimulatory G protein α subunit) and forskolin (except AC9, [29]). adenosine and its derivatives (e.g. 2\u27,5\u27-dideoxyadenosine), acting through the P-site,are inhibitors of adenylyl cyclase activity [36]. Four families of membranous adenylyl cyclase are distinguishable: calmodulin-stimulated (AC1, AC3 and AC8), Ca2+- and Gβγ-inhibitable (AC5, AC6 and AC9), Gβγ-stimulated and Ca2+-insensitive (AC2, AC4 and AC7), and forskolin-insensitive (AC9) forms. A soluble adenylyl cyclase (AC10) lacks membrane spanning regions and is insensitive to G proteins.It functions as a cytoplasmic bicarbonate (pH-insensitive) sensor [7]
SLC51 family of steroid-derived molecule transporters in GtoPdb v.2025.3
Full text linkThe SLC51 organic solute transporter family of transporters is a pair of heterodimeric proteins which regulate bile salt movements in the small intestine, bile duct, and liver, as part of the enterohepatic circulation [2, 5, 1]. OSTα/OSTβ is also expressed in steroidogenic cells of the brain and adrenal gland, where it may contribute to neurosteroid and steroid sulphate movement [6]. Bile acid and steroid sulphate transport is suggested to be bidirectional, facilitative and independent of sodium, potassium, chloride ions or protons [5, 2]. OSTα/OSTβ heterodimers have been shown to transport [3H]taurocholic acid, [3H]dehydroepiandrosterone sulphate, [3H]estrone-3-sulphate, [3H]pregnenolone sulphate and [3H]dehydroepiandrosterone sulphate[2, 5, 6]. OSTα/OSTβ-mediated transport is inhibited by clofazimine and fidaxomicin [9, 11]. OSTα is suggested to be a seven TM protein, while OSTβ is a single TM \u27ancillary\u27 protein, both of which are thought to have intracellular C-termini [8]. Both proteins function in solute transport [8, 4]. Inherited mutations in OSTα and OSTβ are associated with liver disease and congenital diarrhea in children [10, 7]
Ligand-gated ion channels in GtoPdb v.2025.3
Full text linkLigand-gated ion channels (LGICs) are integral membrane proteins that contain a pore which allows the regulated flow of selected ions across the plasma membrane. Ion flux is passive and driven by the electrochemical gradient for the permeant ions. These channels are open, or gated, by the binding of a neurotransmitter to an orthosteric site(s) that triggers a conformational change that results in the conducting state. Modulation of gating can occur by the binding of endogenous, or exogenous, modulators to allosteric sites. LGICs mediate fast synaptic transmission, on a millisecond time scale, in the nervous system and at the somatic neuromuscular junction. Such transmission involves the release of a neurotransmitter from a pre-synaptic neurone and the subsequent activation of post-synaptically located receptors that mediate a rapid, phasic, electrical signal (the excitatory, or inhibitory, post-synaptic potential). However, in addition to their traditional role in phasic neurotransmission, it is now established that some LGICs mediate a tonic form of neuronal regulation that results from the activation of extra-synaptic receptors by ambient levels of neurotransmitter. The expression of some LGICs by non-excitable cells is suggestive of additional functions.By convention, the LGICs comprise the excitatory, cation-selective, nicotinic acetylcholine [959, 210], 5-HT3 [68, 1441], ionotropic glutamate [856, 1375] and P2X receptors [659, 1330] and the inhibitory, anion-selective, GABAA [1066, 83] and glycine receptors [878, 1539]. The nicotinic acetylcholine, 5-HT3, GABAA and glycine receptors (and an additional zinc-activated channel) are pentameric structures and are frequently referred to as the Cys-loop receptors due to the presence of a defining loop of residues formed by a disulphide bond in the extracellular domain of their constituent subunits [966, 1357]. However, the prokaryotic ancestors of these receptors contain no such loop and the term pentameric ligand-gated ion channel (pLGIC) is gaining acceptance in the literature [573]. The ionotropic glutamate and P2X receptors are tetrameric and trimeric structures, respectively. Multiple genes encode the subunits of LGICs and the majority of these receptors are heteromultimers. Such combinational diversity results, within each class of LGIC, in a wide range of receptors with differing pharmacological and biophysical properties and varying patterns of expression within the nervous system and other tissues. The LGICs thus present attractive targets for new therapeutic agents with improved discrimination between receptor isoforms and a reduced propensity for off-target effects. The development of novel, faster screening techniques for compounds acting on LGICs [359] will greatly aid in the development of such agents