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Leukotriene receptors in GtoPdb v.2025.3
Full text linkThe leukotriene receptors (nomenclature as agreed by the NC-IUPHAR subcommittee on Leukotriene Receptors [36, 39]) are activated by the endogenous ligands leukotrienes (LT), synthesized from lipoxygenase metabolism of arachidonic acid. The human BLT1 receptor is the high affinity LTB4 receptor whereas the BLT2 receptor in addition to being a low-affinity LTB4 receptor also binds several other lipoxygenase-products, such as 12S-HETE, 12S-HPETE, 15S-HETE, and the thromboxane synthase product 12-hydroxyheptadecatrienoic acid. The BLT receptors mediate chemotaxis and immunomodulation in several leukocyte populations and are in addition expressed on non-myeloid cells, such as vascular smooth muscle and endothelial cells. In addition to BLT receptors, LTB4 has been reported to bind to the peroxisome proliferator activated receptor (PPAR) α [206] and the vanilloid TRPV1 ligand-gated nonselective cation channel [228]. The crystal structure of the BLT1 receptor was initially determined in complex with selective antagonists [145, 236] and extended to the cryo-electron microscopy structure of LTB4-bound human BLT1 receptor at 2.91 Å resolution [402]. The receptors for the cysteinyl-leukotrienes (i.e. LTC4, LTD4 and LTE4) are termed CysLT1 and CysLT2 and exhibit distinct expression patterns in human tissues, mediating for example smooth muscle cell contraction, regulation of vascular permeability, and leukocyte activation. The crystal structures of both receptors have been solved; CysLT1 in complex with zafirlukast and pranlukast [208] and CysLT2 in complex with three dual CysLT1/CysLT2 antagonists [126]. There is also evidence in the literature for additional CysLT receptor subtypes, derived from functional in vitro studies, radioligand binding and in mice lacking both CysLT1 and CysLT2 receptors [39]. Cysteinyl-leukotrienes have also been suggested to signal through the P2Y12 receptor [101, 256, 286], GPR17 [60] and the oxoglutarate receptor OXGR1 (previously referred to as GPR99) [177]
Orexin receptors in GtoPdb v.2025.3
Full text linkOrexin receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Orexin receptors [79]) are activated by the endogenous polypeptides orexin-A and orexin-B (also known as hypocretin-1 and -2; 33 and 28 aa) derived from a common precursor, prepro-orexin or orexin precursor, by proteolytic cleavage and some typical peptide modifications [120, 79]. Orexin signaling has been associated with regulation of sleep and wakefulness, reward and addiction, appetite and feeding, pain gating, stress response, anxiety and depression. Currently the orexin receptor ligands in clinical use are the dual orexin receptor antagonists suvorexant, lemborexant and daridorexant, which are used as hypnotics, and several dual, as well as OX1- and OX2-selective antagonists are under development for different indications. Multiple orexin agonists are in development for the treatment of narcolepsy and other sleep disorders. Orexin receptor 3D structures have been solved [150, 148, 55, 130, 47, 113, 7, 149]
3C. 3-Ketosteroid receptors in GtoPdb v.2025.3
Full text linkSteroid hormone receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [75, 221, 3]) are nuclear hormone receptors of the NR3 class, with endogenous agonists that may be divided into 3-hydroxysteroids (estrone and 17β-estradiol) and 3-ketosteroids (dihydrotestosterone [DHT], aldosterone, cortisol, corticosterone, progesterone and testosterone). For rodent GR and MR, the physiological ligand is corticosterone rather than cortisol. Clinically-used drugs interacting with the 3-ketosteroid receptors include testosterone (AR), methylprednisolone (GR), eplerenone (MR), and medroxyprogesterone (PR)
Lysophospholipid (S1P) receptors in GtoPdb v.2025.3
No full textSphingosine 1-phosphate (S1P) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Lysophospholipid receptors [98]) are activated by the endogenous lipid sphingosine 1-phosphate (S1P). Originally cloned as orphan members of the endothelial differentiation gene (edg) family [16, 125], the receptors are currently designated as S1P1R through S1P5R [75, 16, 125]. Their gene nomenclature has been codified as human S1PR1, S1PR2, etc. (HUGO Gene Nomenclature Committee, HGNC) and S1pr1, S1pr2, etc. for mice (Mouse Genome Informatics Database, MGI) to reflect species and receptor function. All S1P receptors (S1PRs) have been knocked-out in mice constitutively and in some cases, conditionally. S1PRs, particularly S1P1, are expressed throughout all mammalian organ systems. Ligand delivery occurs via two known carriers (or "chaperones"): albumin and HDL-bound apolipoprotein M (ApoM), the latter of which elicits biased agonist signaling by S1P1 in multiple cell types [18, 54]. The five S1PRs, two chaperones, and active cellular metabolism have complicated analyses of receptor ligand binding in native systems. Signaling pathways and physiological roles have been characterized through radioligand binding in heterologous expression systems, targeted deletion of the different S1PRs, and most recently, mouse models that report in vivo S1P1R activation [103, 105]. The structures of S1P1 [185, 70, 110, 189], S1P2 [32], S1P3[118, 192], and S1P5 [112, 190] are solved, and confirmed aspects of ligand binding, specificity, and receptor activation, determined previously through biochemical and genetic studies [70, 17]. fingolimod (FTY720), the first FDA-approved drug to target any of the lysophospholipid receptors, binds as a phosphorylated metabolite to four of the five S1PRs, and was the first oral therapy for multiple sclerosis (MS) [35]. Second-generation S1PR modulators siponimod and ozanimod target S1P1 and S1P5, while etrasimod targets S1P1, S1P4 and S1P5; and ponesimod targets S1P1 alone, and all are FDA approved for the treatment of various MS forms [16, 125] and/or ulcerative colitis for ozanimod and etrasimod [147, 158]. The mechanisms of action of fingolimod and other S1PR-modulating drugs now in development include binding S1PRs in multiple organ systems, e.g., immune and nervous systems, although the precise nature of their receptor interactions requires clarification, although most S1P1 effects appear to involve functional antagonism [143, 37, 64, 65]
Cytochrome P450 in GtoPdb v.2025.3
Full text linkThe cytochrome P450 enzyme superfamily (CYP), E.C. 1.14.-.-, are haem-containing monooxygenases with a vast range of both endogenous and exogenous substrates. These include sterols, fatty acids, eicosanoids, fat-soluble vitamins, hormones, pesticides and carcinogens as well as drugs. Listed below are the human enzymes, their relationship with rodent CYP enzyme activities is obscure in that the species orthologue may not metabolise the same substrates. Some of the CYP enzymes located in the liver are particularly important for drug metabolism, both hepatic and extrahepatic CYP enzymes also contribute to patho/physiological processes. Genetic variation of CYP isoforms is widespread and likely underlies a proportion of individual variation in drug disposition. The superfamily has the root symbol CYP, followed by a number to indicate the family, a capital letter for the subfamily with a numeral for the individual enzyme. Some CYP are able to metabolise multiple substrates, others are oligo- or mono- specific. CYP also catalyse diverse oxidation and reduction reactions. These include ring hydroxylation, N-oxidation, sulfoxidation, epoxidation, the dealkylation of N-, S- and O- moieties, desulfation, deamination, as well as reduction of azo, nitro and N-oxide groups
Type VIII RTKs: ROR family in GtoPdb v.2025.3
Full text linkROR1 and ROR2 are involved in regulating Wnt-5a signalling. There is evidence that ROR1 and ROR2 can form heteromeric complexes. Due to their role in cancer, therapies targeting RORs are under investigation. Thus, ROR1 and ROR2 appear to be activated by Wnt-5a binding to a Frizzled receptor thereby forming a cell-surface multiprotein complex [3]
Type XVIII RTKs: LMR family in GtoPdb v.2025.3
Full text linkThe lemur tail kinase (LMR) family are are unusual amongst the RTKs in possessing a short extracellular domain and extended intracellular domain (hence the \u27Lemur\u27 name reflecting the long tail). LMR1 was identified as a potential marker of apoptosis [2], giving rise to the name AATYK (Apoptosis-Associated Tyrosine Kinase); while over-expression induces differentiation in neuroblastoma cells [3]. The LMTK/LMR family have since been identified to have serine/threonine kinase activity, as opposed to tyrosine kinase [4]
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
Carnitine palmitoyltransferases in GtoPdb v.2025.3
Full text linkThe CPT1 enzymes convert long chain (greater than ∼C12) acyl-CoA molecules to acylcarnitine derivatives to facilitate their transport from the cytosol into the mitochondrial matrix via the carnitine/acylcarnitine carrier (CACT; SLC25A20). The acylcarnitines are converted back to acyl-CoA by CPT2 to support the fatty acid oxidation (FAO) cycle in the mitochondria. CPT1s are allosterically inhibited by malonyl-CoA
Two-pore domain potassium channels (K2P) in GtoPdb v.2025.4
Full text linkThe 4TM family of K channels mediate many of the background potassium currents observed in native cells. They are open across the physiological voltage-range and are regulated by a wide array of neurotransmitters and biochemical mediators. The pore-forming α-subunit contains two pore loop (P) domains and two subunits assemble to form one ion conduction pathway lined by four P domains. It is important to note that single channels do not have two pores but that each subunit has two P domains in its primary sequence; hence the name two-pore domain, or K2P channels (and not two-pore channels). Some of the K2P subunits can form heterodimers across subfamilies (e.g. K2P3.1 with K2P9.1). The nomenclature of 4TM K channels in the literature is still a mixture of IUPHAR and common names. The suggested division into subfamilies, described in the more detailed introduction, is based on similarities in both structural and functional properties within subfamilies and this explains the "common abbreviation" nomenclature in the tables below