IUPHAR/BPS Guide to Pharmacology CITE
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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
Tumour necrosis factor (TNF) receptor family in GtoPdb v.2025.3
Full text linkThe TNF receptor family has at least 29 genes, with diverse roles in cell death, inflammation and development. Dysregulated TNFR signalling is associated with many inflammatory disorders, including some forms of arthritis and inflammatory bowel disease, and targeting TNF has been an effective therapeutic strategy in these diseases and for cancer immunotherapy [5, 6, 53]
Endocannabinoid turnover in GtoPdb v.2025.3
Full text linkThe principle endocannabinoids are 2-acylglycerol esters, such as 2-arachidonoylglycerol (2-AG), and N-acylethanolamines, such as anandamide (N-arachidonoylethanolamine, AEA). The glycerol esters and ethanolamides are synthesised and hydrolysed by parallel, independent pathways. Mechanisms for release and re-uptake of endocannabinoids are unclear, although potent and selective inhibitors of facilitated diffusion of endocannabinoids across cell membranes have been developed [32]. FABP5 (Q01469) has been suggested to act as a canonical intracellular endocannabinoid transporter in vivo [19]. For the generation of 2-arachidonoylglycerol, the key enzyme involved is diacylglycerol lipase (DAGL), whilst several routes for anandamide synthesis have been described, the best characterized of which involves N-acylphosphatidylethanolamine-phospholipase D (NAPE-PLD, [79]). A transacylation enzyme which forms N-acylphosphatidylethanolamines has been identified as a cytosolic enzyme, PLA2G4E (Q3MJ16) [70]. In vitro experiments indicate that the endocannabinoids are also substrates for oxidative metabolism via cyclooxygenase, lipoxygenase and cytochrome P450 enzyme activities [6, 26, 81]
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
Voltage-gated potassium channels (Kv) in GtoPdb v.2025.4
Full text linkThe 6TM family of K channels comprises the voltage-gated KV subfamilies, the EAG subfamily (which includes hERG channels), the Ca2+-activated Slo subfamily (actually with 7TM, termed BK) and the Ca2+-activated SK subfamily. These channels possess a pore-forming α subunit that comprises tetramers of identical subunits (homomeric) or of different subunits (heteromeric). Heteromeric channels can only be formed within subfamilies (e.g. Kv1.1 with Kv1.2; Kv7.2 with Kv7.3). The pharmacology largely reflects the subunit composition of the functional channel.Kv7 channelsKv7.1-Kv7.5 (KCNQ1-5) K+ channels are voltage-gated K+ channels with major roles in neurons, muscle cells and epithelia where they underlie physiologically important K+ currents, such as the neuronal M-current and the cardiac IKs. Genetic deficiencies in all five KCNQ genes result in human excitability disorders, including epilepsy, autism spectrum disorders, cardiac arrhythmias and deafness. Thanks to the recent knowledge of the structure and function of human KCNQ-encoded proteins, these channels are increasingly used as drug targets for treating diseases [333, 2, 777, 294]
Voltage-gated sodium channels (NaV) in GtoPdb v.2025.4
Full text linkSodium channels are voltage-gated sodium-selective ion channels present in the membrane of most excitable cells. Sodium channels comprise 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])
Bombesin receptors in GtoPdb v.2025.3
Full text linkMammalian bombesin (Bn) receptors comprise 3 subtypes: BB1, BB2, BB3 (nomenclature recommended by the NC-IUPHAR Subcommittee on bombesin receptors, [118, 5]). BB1 and BB2 are activated by the endogenous ligands neuromedin B (NMB), gastrin-releasing peptide (GRP), and GRP-(18-27). bombesin is a tetra-decapeptide, originally derived from amphibians and structurally closely related to GRP. The three Bn receptor subtypes couple primarily to the Gq/11 and G12/13 family of G proteins [118]. Each of these receptors is widely distributed in the CNS and peripheral tissues [81, 118, 259, 288, 373, 115, 6, 375, 125, 204]. Activation of BB1 and BB2 receptors causes a wide range of physiological/pathophysiogical actions, including the stimulation of normal and neoplastic tissue growth, smooth-muscle contraction, respiration, gastrointestinal motility, feeding behavior, secretion and many central nervous system effects including regulation of circadian rhythm, body temperature control, sighing, behavioral disorders and mediation of pruritus [210, 118, 204, 259, 211, 37, 375, 211, 44, 4]. BB3 is an orphan receptor, although some propose it is constitutively active [328]. BB3 receptor knockout studies show it has important roles in glucose and insulin regulation, metabolic homeostasis, feeding, regulation of body temperature, obesity, diabetes mellitus and growth of normal/neoplastic tissues [154, 81, 223, 208, 4, 208]. Bn receptors are one of the most frequently overexpressed receptors in cancers and are receiving increased attention for their roles in tumor growth, as well as for tumour imaging and for receptor-targeted cytotoxicity especially for advanced prostate and breast cancer [210, 167, 13, 136, 377, 371]. Bn receptors are also receiving attention because they are one of the primary neurotransmitters for pruritus [37, 128, 240]
Class A Orphans in GtoPdb v.2025.3
Full text linkTable 1 lists a number of putative GPCRs identified by NC-IUPHAR [206], for which preliminary evidence for an endogenous ligand has been published, or for which there exists a potential link to a disease, or disorder. These GPCRs have recently been reviewed in detail [156]. The GPCRs in Table 1 are all Class A, rhodopsin-like GPCRs. Class A orphan GPCRs not listed in Table 1 are putative GPCRs with as-yet unidentified endogenous ligands.Table 1: Class A orphan GPCRs with putative endogenous ligands GPR3GPR4GPR6GPR12GPR15GPR17GPR20 GPR22GPR26GPR31GPR34GPR35GPR37GPR39 GPR50GPR63GPR65GPR68GPR75GPR84GPR87 GPR88GPR132GPR149GPR161GPR183LGR4LGR5 LGR6MAS1MRGPRDMRGPRX1MRGPRX2P2RY10TAAR2 In addition the orphan receptors GPR18, GPR55 and GPR119 which are reported to respond to endogenous agents analogous to the endogenous cannabinoid ligands have been grouped together (GPR18, GPR55 and GPR119)
Class C Orphans in GtoPdb v.2025.3
Full text linkThis set contains class C \u27orphan\u27 G protein coupled receptors where the endogenous ligand(s) is not known
Class Frizzled GPCRs in GtoPdb v.2025.3
Full text linkReceptors of the Class Frizzled (FZD, nomenclature as agreed by the NC-IUPHAR subcommittee on the Class Frizzled GPCRs [184]), are GPCRs highly conserved across species and were originally identified in Drosophila [21]. While SMO shows structural resemblance to the 10 FZDs, it is functionally separated as it is involved in Hedgehog signaling [184]. SMO exerts its effects by activating heterotrimeric G proteins or stabilization of GLI by sequestering catalytic PKA subunits [191, 6, 62]. While SMO itself is bound by sterols and oxysterols [28, 96], FZDs are activated by WNTs, which are cysteine-rich lipoglycoproteins with fundamental functions in ontogeny and tissue homeostasis. FZD signaling was initially divided into two pathways, being either dependent on the accumulation of the transcription regulator β-catenin or being β-catenin-independent (often referred to as canonical vs. non-canonical WNT/FZD signaling, respectively). Nevertheless, it makes pharmacologically more sense to define downstream signaling by transducer coupling to either DVL or heterotrimeric G proteins [185]. WNT stimulation of FZDs can, in cooperation with the low density lipoprotein receptors LRP5 (O75197) and LRP6 (O75581), lead to the inhibition of a constitutively active destruction complex, which results in the accumulation of β-catenin and subsequently its translocation to the nucleus. β-catenin, in turn, modifies gene transcription by interacting with TCF/LEF transcription factors. WNT/β-catenin-dependent signalling can also be activated by FZD subtype-specific WNT surrogates [142]. β-catenin-independent FZD signalling is far more complex with regard to the diversity of the activated pathways. WNT/FZD signalling can lead to the activation of heterotrimeric G proteins [35, 188, 159], the elevation of intracellular calcium [194], activation of cGMP-specific PDE6 [2] and elevation of cAMP as well as RAC-1, JNK, Rho and Rho kinase signalling [61]. Novel resonance energy transfer-based tools have allowed the study of the GPCR-like nature of FZDs in greater detail. Upon ligand stimulation, FZDs undergo conformational changes and signal via heterotrimeric G proteins [248, 249, 110, 183, 108, 56, 13]. Furthermore, the phosphoprotein Dishevelled constitutes a key transducer in WNT/FZD signaling towards planar-cell-polarity-like pathways. Importantly, FZDs adopt distinct conformational landscapes that regulate pathway selection [249, 54]. As with other GPCRs, members of the Frizzled family are functionally dependent on the arrestin scaffolding protein for internalization [24], as well as for β-catenin-dependent [15] and -independent [93, 16] signalling. The pattern of cell signalling is complicated by the presence of additional ligands, which can enhance or inhibit FZD signalling (secreted Frizzled-related proteins (sFRP), Wnt-inhibitory factor (WIF), sclerostin or Dickkopf (DKK)), as well as modulatory (co)-receptors with Ryk, ROR1, ROR2 and PTK7, which may also function as independent signaling proteins. An important FZD4-selective non-WNT agonist is the norrin cysteine knot protein, which is a key player in FZD4-mediated vascularization for example in the retina and which is functionally related to familial exudative vitreoretinopathy (FEVR)