IUPHAR/BPS Guide to Pharmacology CITE
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5-HT3 receptors in GtoPdb v.2025.3
Full text linkThe 5-HT3 receptor (nomenclature as agreed by the NC-IUPHAR Subcommittee on 5-Hydroxytryptamine (serotonin) receptors [72]) is a ligand-gated ion channel of the Cys-loop family that includes the zinc-activated channels, nicotinic acetylcholine, GABAA and strychnine-sensitive glycine receptors. The receptor exists as a pentamer of 4 transmembrane (TM) subunits that form an intrinsic cation selective channel [7], but may also form intermediary tetramers in the cell membrane during assembly [83]. Five human 5-HT3 receptor subunits have been cloned and homo-oligomeric assemblies of 5-HT3A and hetero-oligomeric assemblies of 5-HT3A and 5-HT3B subunits have been characterised in detail. The 5-HT3C (HTR3C, Q8WXA8), 5-HT3D (HTR3D, Q70Z44) and 5-HT3E (HTR3E, A5X5Y0) subunits [90, 131], like the 5-HT3B subunit, do not form functional homomers, but are reported to assemble with the 5-HT3A subunit to influence its functional expression rather than pharmacological profile [133, 69, 167]. 5-HT3A, -C, -D, and -E subunits also interact with the chaperone RIC-3 which predominantly enhances the surface expression of homomeric 5-HT3A receptor [167, 41]. The co-expression of 5-HT3A and 5-HT3C-E subunits has been demonstrated in human colon [89]. A recombinant hetero-oligomeric 5-HT3AB receptor has been reported to contain two copies of the 5-HT3A subunit and three copies of the 5-HT3B subunit in the order B-B-A-B-A [9], but this is inconsistent with recent reports which show at least one A-A interface [104, 160]. The 5-HT3B subunit imparts distinctive biophysical properties upon hetero-oligomeric 5-HT3AB versus homo-oligomeric 5-HT3A recombinant receptors [36, 46, 62, 92, 149, 138, 86], influences the potency of channel blockers, but generally has only a modest effect upon the apparent affinity of agonists, or the affinity of antagonists ([19], but see [46, 34, 39]) which may be explained by the orthosteric binding site residing at an interface formed between 5-HT3A subunits [104, 160]. However, 5-HT3A and 5-HT3AB receptors differ in their allosteric regulation by some general anaesthetic agents, small alcohols and indoles [148, 145, 76]. The potential diversity of 5-HT3 receptors is increased by alternative splicing of the genes HTR3A and HTR3E [70, 22, 133, 132, 129]. In addition, the use of tissue-specific promoters driving expression from different transcriptional start sites has been reported for the HTR3A, HTR3B, HTR3D and HTR3E genes, which could result in 5-HT3 subunits harbouring different N-termini [162, 86, 129]. To date, inclusion of the 5-HT3A subunit appears imperative for 5-HT3 receptor function
Voltage-gated sodium channels (NaV) in GtoPdb v.2025.3
Full text linkSodium channels are voltage-gated sodium-selective ion channels present in the membrane of most excitable cells. Sodium channels comprise of one pore-forming α subunit, which may be associated with either one or two β subunits [191]. α-Subunits consist of four homologous domains (I-IV), each containing six transmembrane segments (S1-S6) and a pore-forming loop. The positively charged fourth transmembrane segment (S4) acts as a voltage sensor and is involved in channel gating. The crystal structure of the bacterial NavAb channel has revealed a number of novel structural features compared to earlier potassium channel structures including a short selectivity filter with ion selectivity determined by interactions with glutamate side chains [298]. Interestingly, the pore region is penetrated by fatty acyl chains that extend into the central cavity which may allow the entry of small, hydrophobic pore-blocking drugs [298]. Auxiliary β1, β2, β3 and β4 subunits consist of a large extracellular N-terminal domain, a single transmembrane segment and a shorter cytoplasmic domain. Pharmacological targeting of voltage-gated sodium channels has long been a cornerstone of clinical treatment for a range of conditions. Classical sodium channel blockers, many of which act by occluding the central pore, are widely used as local anesthetics, antiarrhythmic agents, and anticonvulsants [135]. More recently, suzetrigine, a highly selective Nav1.8 inhibitor, received FDA approval for the treatment of acute post-operative pain [202, 419]. The nomenclature for sodium channels was proposed by Goldin et al., (2000) [155] and approved by the NC-IUPHAR Subcommittee on sodium channels (Catterall et al., 2005, [54])
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]
Eicosanoid turnover in GtoPdb v.2025.1
Full text linkEicosanoids are 20-carbon fatty acids, where the usual focus is the polyunsaturated analogue arachidonic acid and its metabolites. Arachidonic acid is thought primarily to derive from phospholipase A2 action on membrane phosphatidylcholine, and may be re-cycled to form phospholipid through conjugation with coenzyme A and subsequently glycerol derivatives. Oxidative metabolism of arachidonic acid is conducted through three major enzymatic routes: cyclooxygenases; lipoxygenases and cytochrome P450-like epoxygenases, particularly CYP2J2. Isoprostanes are structural analogues of the prostanoids (hence the nomenclature D-, E-, F-isoprostanes and isothromboxanes), which are produced in the presence of elevated free radicals in a non-enzymatic manner, leading to suggestions for their use as biomarkers of oxidative stress. Molecular targets for their action have yet to be defined
Dopamine receptors in GtoPdb v.2025.3
Full text linkDopamine receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Dopamine Receptors [375]) are commonly divided into D1-like (D1 and D5) and D2-like (D2, D3 and D4) families, where the endogenous agonist is dopamine
Free fatty acid receptors in GtoPdb v.2025.3
Full text linkFree fatty acid receptors (FFA, nomenclature as agreed by the NC-IUPHAR Subcommittee on free fatty acid receptors [118, 27]) are activated by free fatty acids. Long-chain saturated and unsaturated fatty acids (including C14.0 (myristic acid), C16:0 (palmitic acid), C18:1 (oleic acid), C18:2 (linoleic acid), C18:3, (α-linolenic acid), C20:4 (arachidonic acid), C20:5,n-3 (EPA) and C22:6,n-3 (docosahexaenoic acid)) activate FFA1 [9, 54, 65] and FFA4 receptors [45, 52, 96], while short chain fatty acids (C2 (acetic acid), C3 (propanoic acid), C4 (butyric acid) and C5 (pentanoic acid)) activate FFA2 [10, 67, 92] and FFA3 [10, 67] receptors. The crystal structure for agonist bound FFA1 has been described [115]
Lysophospholipid (LPA) receptors in GtoPdb v.2025.3
Full text linkLysophosphatidic acid (LPA) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Lysophospholipid Receptors [67, 27, 96, 151]) are activated by the endogenous phospholipid LPA. The first receptor, LPA1, was identified as ventricular zone gene-1 (vzg-1) [52], This discovery represented the beginning of the de-orphanisation of members of the endothelial differentiation gene (edg) family, as other LPA and sphingosine 1-phosphate (S1P) receptors were found. Five additional LPA receptors (LPA2,3,4,5,6) have since been identified [96] and their gene nomenclature codified for human LPAR1, LPAR2, etc. (HUGO Gene Nomenclature Committee, HGNC) and Lpar1, Lpar2, etc. for mice (Mouse Genome Informatics Database, MGI) to reflect species and receptor function of their corresponding proteins. The high-resolution structures of LPA1 [3, 20, 86, 4] and LPA6 [31, 135] determined by both X-ray crystallography and cryo-electron microscopy, are solved and indicate that LPA accesses the extracellular binding pocket, consistent with its proposed delivery via autotaxin [20]. These studies have also implicated crosstalk with endocannabinoids via phosphorylated intermediates that can also activate these receptors. The binding affinities to LPA1 of unlabeled, natural LPA and anandamide phosphate (AEAp) were measured using backscattering interferometry (pKd = 9) [97, 121]. Utilization of this method indicated affinities that were 77-fold lower than when measured using radioactivity-based protocols [150]. Targeted deletion of LPA receptors has clarified signalling pathways and identified physiological and pathophysiological roles. admilparant (BMS-986278) [25], a selective LPA1 receptor antagonist, is currently in Phase III trials for pulmonary fibrosis. Other LPA1-targeting drugs such as BMS-986020 were discontinued due to hepatotoxicity [110], while preclinical candidates like PIPE 791 [119] are being explored for neurological and fibrotic diseases. Multiple groups have independently published validation of all six LPA receptors described in these tables, and further validation was achieved using a distinct read-out via a novel TGFα "shedding" assay [60]. Moreover, LPA has also been described as an agonist for the transient receptor potential (Trp) ion channels TRPV1 [101] and TRPA1 [70]. All of these proposed non-GPCR receptor identities require confirmation and are not currently recognized as bona fide LPA receptors
Tachykinin receptors in GtoPdb v.2025.3
Full text linkTachykinin receptors (provisional nomenclature as recommended by NC-IUPHAR [91]) are activated by the endogenous peptides substance P (SP), neurokinin A (NKA; previously known as substance K, neurokinin α, neuromedin L), neurokinin B (NKB; previously known as neurokinin β, neuromedin K), neuropeptide K and neuropeptide γ (N-terminally extended forms of neurokinin A). The neurokinins (A and B) are mammalian members of the tachykinin family, which includes peptides of mammalian and nonmammalian origin containing the consensus sequence: Phe-x-Gly-Leu-Met. Marked species differences in in vitro pharmacology exist for all three receptors, in the context of nonpeptide ligands. Antagonists such as aprepitant and fosaprepitant were approved by FDA and EMA, in combination with other antiemetic agents, for the prevention of nausea and vomiting associated with emetogenic cancer chemotherapy
Voltage-gated calcium channels (CaV) in GtoPdb v.2025.3
Full text linkCa2+ channels are voltage-gated ion channels present in the membrane of most excitable cells. The nomenclature for Ca2+channels was proposed by [136] and approved by the NC-IUPHAR Subcommittee on Ca2+ channels [75]. Most Ca2+ channels form hetero-oligomeric complexes. The α1 subunit is pore-forming and provides the binding site(s) for practically all agonists and antagonists. The 10 cloned α1-subunits can be grouped into three families: (1) the high-voltage activated dihydropyridine-sensitive (L-type, CaV1.x) channels; (2) the high- to moderate-voltage activated dihydropyridine-insensitive (CaV2.x) channels and (3) the low-voltage-activated (T-type, CaV3.x) channels. Each α1 subunit has four homologous repeats (I-IV), each repeat having six transmembrane domains (S1-S6) forming a voltage-sensing domain (VSD, S1-S4) coupled to a pore-forming module (S5, S6 and their connecting linker that contains the selectivity filter. Voltage-dependent gating is driven by voltage-induced transmembrane movements of the S4-helix enabled by conserved positive charges interacting with negative counter-charges within the VSD [74]. All of the α1-subunit genes give rise to alternatively spliced products. At least for high-voltage activated channels, it is likely that native channels comprise co-assemblies of α1, β and α2-δ subunits. CACHD1 is an α2δ-like protein that modulates Cav3 channel activity [100]. The γ subunits have not been proven to associate with channels other than the α1s skeletal muscle Cav1.1 channel. The α2-δ1 and α2-δ2 subunits bind gabapentin and pregabalin [92]
SLC14 family of facilitative urea transporters in GtoPdb v.2025.3
Full text linkAs a product of protein catabolism, urea is moved around the body and through the kidneys for excretion. Although there is experimental evidence for concentrative urea transporters, these have not been defined at the molecular level. The SLC14 family are facilitative transporters, allowing urea movement down its concentration gradient. Multiple splice variants of these transporters have been identified; for UT-A transporters, in particular, there is evidence for cell-specific expression of these variants with functional impact [5, 1]. Topographical modelling suggests that the majority of the variants of SLC14 transporters have 10 TM domains, with a glycosylated extracellular loop at TM5/6, and intracellular C- and N-termini. The UT-A1 splice variant, exceptionally, has 20 TM domains, equivalent to a combination of the UT-A2 and UT-A3 splice variants