IUPHAR/BPS Guide to Pharmacology CITE最新文献

{"title":"Metabotropic glutamate receptors in GtoPdb v.2023.1","authors":"F. Acher, G. Battaglia, H. Bräuner‐Osborne, P. Conn, R. Duvoisin, F. Ferraguti, P. Flor, C. Goudet, K. Gregory, D. Hampson, Michael P. Johnson, Y. Kubo, J. Monn, S. Nakanishi, F. Nicoletti, C. Niswender, J. Pin, P. Rondard, D. Schoepp, R. Shigemoto, M. Tateyama","doi":"10.2218/gtopdb/f40/2023.1","DOIUrl":"https://doi.org/10.2218/gtopdb/f40/2023.1","url":null,"abstract":"Metabotropic glutamate (mGlu) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Metabotropic Glutamate Receptors [351]) are a family of G protein-coupled receptors activated by the neurotransmitter glutamate [140]. The mGlu family is composed of eight members (named mGlu1 to mGlu8) which are divided in three groups based on similarities of agonist pharmacology, primary sequence and G protein coupling to effector: Group-I (mGlu1 and mGlu5), Group-II (mGlu2 and mGlu3) and Group-III (mGlu4, mGlu6, mGlu7 and mGlu8) (see Further reading).Structurally, mGlu are composed of three juxtaposed domains: a core G protein-activating seven-transmembrane domain (TM), common to all GPCRs, is linked via a rigid cysteine-rich domain (CRD) to the Venus Flytrap domain (VFTD), a large bi-lobed extracellular domain where glutamate binds. mGlu form constitutive dimers, cross-linked by a disulfide bridge. The structures of the VFTD of mGlu1, mGlu2, mGlu3, mGlu5 and mGlu7 have been solved [200, 275, 268, 403]. The structure of the 7 transmembrane (TM) domains of both mGlu1 and mGlu5 have been solved, and confirm a general helical organisation similar to that of other GPCRs, although the helices appear more compacted [88, 433, 62]. Recent advances in cryo-electron microscopy have provided structures of full-length mGlu receptor homodimers [217, 191] and heterodimers [91]. Studies have revealed the possible formation of heterodimers between either group-I receptors, or within and between group-II and -III receptors [89]. First characterised in transfected cells, co-localisation and specific pharmacological properties suggest the existence of such heterodimers in the brain [270, 440, 145, 283, 259, 218]. Beyond heteromerisation with other mGlu receptor subtypes, increasing evidence suggests mGlu receptors form heteromers and larger order complexes with class A GPCRs (reviewed in [140]). The endogenous ligands of mGlu are L-glutamic acid, L-serine-O-phosphate, N-acetylaspartylglutamate (NAAG) and L-cysteine sulphinic acid. Group-I mGlu receptors may be activated by 3,5-DHPG and (S)-3HPG [30] and antagonised by (S)-hexylhomoibotenic acid [235]. Group-II mGlu receptors may be activated by LY389795 [269], LY379268 [269], eglumegad [354, 434], DCG-IV and (2R,3R)-APDC [355], and antagonised by eGlu [170] and LY307452 [425, 105]. Group-III mGlu receptors may be activated by L-AP4 and (R,S)-4-PPG [130]. An example of an antagonist selective for mGlu receptors is LY341495, which blocks mGlu2 and mGlu3 at low nanomolar concentrations, mGlu8 at high nanomolar concentrations, and mGlu4, mGlu5, and mGlu7 in the micromolar range [185]. In addition to orthosteric ligands that directly interact with the glutamate recognition site, allosteric modulators that bind within the TM domain have been described. Negative allosteric modulators are listed separately. The positive allosteric modulators most often act as ‘potentiators’ of an orthosteric agonist response, without signif","PeriodicalId":14617,"journal":{"name":"IUPHAR/BPS Guide to Pharmacology CITE","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84720484","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SLC31 family of copper transporters in GtoPdb v.2023.1","authors":"S. Lutsenko","doi":"10.2218/gtopdb/f218/2023.1","DOIUrl":"https://doi.org/10.2218/gtopdb/f218/2023.1","url":null,"abstract":"SLC31 family members, alongside the Cu-ATPases are involved in the regulation of cellular copper levels. The CTR1 transporter is a cell-surface transporter to allow monovalent copper accumulation into cells, while CTR2 appears to be a vacuolar/vesicular transporter [5]. Functional copper transporters appear to be trimeric with each subunit having three TM regions and an extracellular N-terminus. CTR1 is considered to be a higher affinity copper transporter compared to CTR2. The stoichiometry of copper accumulation is unclear, but appears to be energy-independent [4].","PeriodicalId":14617,"journal":{"name":"IUPHAR/BPS Guide to Pharmacology CITE","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91288296","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prokineticin receptors in GtoPdb v.2023.1","authors":"R. Hills, Adam J. Pawson, P. Rondard, O. Sbai, Q. Zhou","doi":"10.2218/gtopdb/f56/2023.1","DOIUrl":"https://doi.org/10.2218/gtopdb/f56/2023.1","url":null,"abstract":"Prokineticin receptors, PKR1 and PKR2 (provisional nomenclature as recommended by NC-IUPHAR [26]) respond to the cysteine-rich 81-86 amino-acid peptides prokineticin-1 (also known as endocrine gland-derived vascular endothelial growth factor, mambakine) and prokineticin-2 (protein Bv8 homologue). An orthologue of PROK1 from black mamba (Dendroaspis polylepis) venom, mamba intestinal toxin 1 (MIT1, [71]) is a potent, non-selective agonist at prokineticin receptors [46], while Bv8, an orthologue of PROK2 from amphibians (Bombina sp., [49]), is equipotent at recombinant PKR1 and PKR2 [53], and has high potency in macrophage chemotaxis assays, which are lost in PKR1-null mice.","PeriodicalId":14617,"journal":{"name":"IUPHAR/BPS Guide to Pharmacology CITE","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91517619","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"P2Y receptors in GtoPdb v.2023.1","authors":"M. Abbracchio, J. Boeynaems, J. Boyer, G. Burnstock, S. Ceruti, M. Fumagalli, C. Gachet, R. Hills, R. G. Humphries, Kazu Inoue, K. Jacobson, C. Kennedy, B. King, D. Lecca, C. Müller, M. Miras-Portugal, V. Ralevic, G. Weisman","doi":"10.2218/gtopdb/f52/2023.1","DOIUrl":"https://doi.org/10.2218/gtopdb/f52/2023.1","url":null,"abstract":"P2Y receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on P2Y Receptors [3, 5, 189]) are activated by the endogenous ligands ATP, ADP, UTP, UDP, UDP-glucose and adenosine. 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 [380]. 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 [380]. 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 [238], and the P2Y12 receptor antagonists prasugrel, ticagrelor and cangrelor, all approved as antiplatelet drugs [52, 320].","PeriodicalId":14617,"journal":{"name":"IUPHAR/BPS Guide to Pharmacology CITE","volume":"31 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79896496","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nitric oxide synthases in GtoPdb v.2023.1","authors":"T. Billiar, G. Cirino, David Fulton, R. Motterlini, A. Papapetropoulos, Csaba Szabo","doi":"10.2218/gtopdb/f253/2023.1","DOIUrl":"https://doi.org/10.2218/gtopdb/f253/2023.1","url":null,"abstract":"Nitric oxide synthases (NOS, E.C. 1.14.13.39) are a family of oxidoreductases that synthesize nitric oxide (NO.) via the NADPH and oxygen-dependent consumption of L-arginine with the resultant by-product, L-citrulline. There are 3 NOS isoforms and they are related by their capacity to produce NO, highly conserved organization of functional domains and significant homology at the amino acid level. NOS isoforms are functionally distinguished by the cell type where they are expressed, intracellular targeting and transcriptional and post-translation mechanisms regulating enzyme activity. The nomenclature suggested by NC-IUPHAR of NOS I, II and III [12] has not gained wide acceptance, and the 3 isoforms are more commonly referred to as neuronal NOS (nNOS), inducible NOS (iNOS) and endothelial NOS (eNOS) which reflect the location of expression (nNOS and eNOS) and inducible expression (iNOS). All are dimeric enzymes that shuttle electrons from NADPH, which binds to a C-terminal reductase domain, through the flavins FAD and FMN to the oxygenase domain of the other monomer to enable the BH4-dependent reduction of heme bound oxygen for insertion into the substrate, L-arginine. Electron flow from reductase to oxygenase domain is controlled by calmodulin binding to canonical calmodulin binding motif located between these domains. eNOS and nNOS isoforms are activated at concentrations of calcium greater than 100 nM, while iNOS shows higher affinity for Ca2+/calmodulin with great avidity and is essentially calcium-independent and constitutively active. Efficient stimulus-dependent coupling of nNOS and eNOS is achieved via subcellular targeting through respective N-terminal PDZ and fatty acid acylation domains whereas iNOS is largely cytosolic and function is independent of intracellular location. nNOS is primarily expressed in the brain and neuronal tissue, iNOS in immune cells such as macrophages and eNOS in the endothelial layer of the vasculature although exceptions in other cells have been documented. L-NAME and related modified arginine analogues are inhibitors of all three isoforms, with IC50 values in the micromolar range.","PeriodicalId":14617,"journal":{"name":"IUPHAR/BPS Guide to Pharmacology CITE","volume":"175 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77470955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Voltage-gated potassium channels (Kv) in GtoPdb v.2023.1","authors":"B. Attali, K. Chandy, M. Giese, S. Grissmer, G. Gutman, L. Jan, M. Lazdunski, D. Mckinnon, J. Nerbonne, L. Pardo, Gail A. Robertson, B. Rudy, M. Sanguinetti, W. Stühmer, J. Trimmer, Xiaoliang Wang","doi":"10.2218/gtopdb/f81/2023.1","DOIUrl":"https://doi.org/10.2218/gtopdb/f81/2023.1","url":null,"abstract":"The 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 comprise 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 [326, 2, 767].","PeriodicalId":14617,"journal":{"name":"IUPHAR/BPS Guide to Pharmacology CITE","volume":"21 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79029733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lysophospholipid (S1P) receptors in GtoPdb v.2023.1","authors":"Victoria Blaho, Jerold Chun, Deron Herr, Danielle Jones, Deepa Jonnalagadda, Yasuyuki Kihara","doi":"10.2218/gtopdb/f135/2023.1","DOIUrl":"https://doi.org/10.2218/gtopdb/f135/2023.1","url":null,"abstract":"Sphingosine 1-phosphate (S1P) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Lysophospholipid receptors [96]) are activated by the endogenous lipid sphingosine 1-phosphate (S1P). Originally cloned as orphan members of the endothelial differentiation gene (edg) family [16, 123], the receptors are currently designated as S1P1R through S1P5R [73, 16, 123]. 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, 53]. 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 [101, 103]. The structures of S1P1 [180, 69, 108, 184], S1P2 [32], S1P3[116, 187], and S1P5 [110, 185] are solved, and confirmed aspects of ligand binding, specificity, and receptor activation, determined previously through biochemical and genetic studies [69, 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, ozanimod, and ponesimod that target S1P1 and S1P5 are also FDA approved for the treatment of various MS forms [16, 123]. In 2021, ozanimod became the first S1PR modulator to be FDA approved for the treatment of ulcerative colitis [145]. 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 [141, 37, 63, 64].","PeriodicalId":14617,"journal":{"name":"IUPHAR/BPS Guide to Pharmacology CITE","volume":"56 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135016703","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acid-sensing (proton-gated) ion channels (ASICs) in GtoPdb v.2023.1","authors":"Stephan Kellenberger, Lachlan D. Rash","doi":"10.2218/gtopdb/f118/2023.1","DOIUrl":"https://doi.org/10.2218/gtopdb/f118/2023.1","url":null,"abstract":"Acid-sensing ion channels (ASICs, nomenclature as agreed by NC-IUPHAR [48, 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 Caenorhabitis elegans, channels in Drosophila melanogaster and 'orphan' channels that include BLINaC [70] and INaC [72] that have also been named BASICs, for bile acid-activated ion channels [90]. ASIC subunits contain 2 TM domains and assemble as homo- or hetero-trimers [45, 41, 7, 94, 93, 77] 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 [44, 89, 48, 69, 23]). Splice variants of ASIC1 [termed ASIC1a (ASIC, ASICα, BNaC2α) [84], ASIC1b (ASICβ, BNaC2β) [19] and ASIC1b2 (ASICβ2) [79]; note that ASIC1a is also permeable to Ca2+], ASIC2 [termed ASIC2a (MDEG1, BNaC1α, BNC1α) [66, 85, 40] and ASIC2b (MDEG2, BNaC1β) [56]] 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) [83] 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 [58]. 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, 43, 34, 54]. 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 [27]. ASICs have also been detected in taste receptor cells (ASIC1-3)), 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 [55, 28, 42]). A neurotransmitter-like function of protons has been suggested, involving postsynaptically located ASICs of the CNS in functions such as learning and fear perception [35, 50, 97], responses to focal ischemia [91] and to axonal degeneration in autoimmune inflammation in a mouse model of multiple sclerosis [39], as well as seizures [98] and pain [89, 29, 30, 13, 32]. 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 [56, 5, 38, 11]. In ge","PeriodicalId":14617,"journal":{"name":"IUPHAR/BPS Guide to Pharmacology CITE","volume":"259 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135018171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adenosine turnover in GtoPdb v.2023.1","authors":"Detlev Boison","doi":"10.2218/gtopdb/f248/2023.1","DOIUrl":"https://doi.org/10.2218/gtopdb/f248/2023.1","url":null,"abstract":"A multifunctional, ubiquitous molecule, adenosine acts at cell-surface G protein-coupled receptors, as well as numerous enzymes, including protein kinases and adenylyl cyclase. Extracellular adenosine is thought to be produced either by export or by metabolism, predominantly through ecto-5’-nucleotidase activity (also producing inorganic phosphate). It is inactivated either by extracellular metabolism via adenosine deaminase (also producing ammonia) or, following uptake by nucleoside transporters, via adenosine deaminase or adenosine kinase (requiring ATP as co-substrate). Intracellular adenosine may be produced by cytosolic 5’-nucleotidases or through S-adenosylhomocysteine hydrolase (also producing L-homocysteine).","PeriodicalId":14617,"journal":{"name":"IUPHAR/BPS Guide to Pharmacology CITE","volume":"41 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135018177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Calcitonin receptors in GtoPdb v.2023.1","authors":"Michael L. Garelja, Debbie Hay, David R. Poyner, Christopher S. Walker","doi":"10.2218/gtopdb/f11/2023.1","DOIUrl":"https://doi.org/10.2218/gtopdb/f11/2023.1","url":null,"abstract":"This receptor family comprises a group of receptors for the calcitonin/CGRP family of peptides. The calcitonin (CT), amylin (AMY), calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on CGRP, AM, AMY, and CT receptors [131, 74, 71]) are generated by the genes CALCR (which codes for the CT receptor, CTR) and CALCRL (which codes for the calcitonin receptor-like receptor, CLR, previously known as CRLR). Their function and pharmacology are altered in the presence of RAMPs (receptor activity-modifying proteins), which are single TM domain proteins of ca. 150 amino acids, identified as a family of three members; RAMP1, RAMP2 and RAMP3. There are splice variants of the CTR; these in turn produce variants of AMY receptors [131], some of which can be potently activated by CGRP. The endogenous agonists are the peptides calcitonin, α-CGRP (formerly known as CGRP-I), β-CGRP (formerly known as CGRP-II), amylin (occasionally called islet-amyloid polypeptide, diabetes-associated polypeptide), adrenomedullin and adrenomedullin 2/intermedin. There are species differences in peptide sequences, particularly for the CTs. CTR-stimulating peptide (CRSP) is another member of the family with selectivity for the CTR but it is not expressed in humans [93]. CLR (calcitonin receptor-like receptor) by itself binds no known endogenous ligand, but in the presence of RAMPs it gives receptors for CGRP, adrenomedullin and adrenomedullin 2/intermedin. There are several approved drugs that target this receptor family, such as pramlintide, erenumab, and the \"gepant\" class of CGRP receptor antagonists. There are also species differences in agonist pharmacology; for example, CGRP displays potent activity at multiple rat and mouse receptors [58, 15]. The summary table only reflects human receptor pharmacology.","PeriodicalId":14617,"journal":{"name":"IUPHAR/BPS Guide to Pharmacology CITE","volume":"22 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135018447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}