{"title":"3A. Estrogen receptors in GtoPdb v.2023.1","authors":"Laurel Coons, Kenneth S. Korach","doi":"10.2218/gtopdb/f96/2023.1","DOIUrl":"https://doi.org/10.2218/gtopdb/f96/2023.1","url":null,"abstract":"Estrogen receptor (ER) activity regulates diverse physiological processes via transcriptional modulation of target genes [2]. The selection of target genes and the magnitude of the response, be it induction or repression, are determined by many factors, including the effect of the hormone ligand and DNA binding on ER structural conformation, and the local cellular regulatory environment. The cellular environment defines the specific complement of DNA enhancer and promoter elements present and the availability of coregulators to form functional transcription complexes. Together, these determinants control the resulting biological response.","PeriodicalId":14617,"journal":{"name":"IUPHAR/BPS Guide to Pharmacology CITE","volume":"18 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":"135016930","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}
Anthony P. Davenport, Birgitte Holst, Matthias Kleinz, Janet J. Maguire, Bjørn B. Sivertsen
{"title":"Ghrelin receptor in GtoPdb v.2023.1","authors":"Anthony P. Davenport, Birgitte Holst, Matthias Kleinz, Janet J. Maguire, Bjørn B. Sivertsen","doi":"10.2218/gtopdb/f28/2023.1","DOIUrl":"https://doi.org/10.2218/gtopdb/f28/2023.1","url":null,"abstract":"The ghrelin receptor (nomenclature as agreed by the NC-IUPHAR Subcommittee for the Ghrelin receptor [19]) is activated by a 28 amino-acid peptide originally isolated from rat stomach, where it is cleaved from a 117 amino-acid precursor (GHRL, Q9UBU3). The human gene encoding the precursor peptide has 83% sequence homology to rat prepro-ghrelin, although the mature peptides from rat and human differ by only two amino acids [75]. Alternative splicing results in the formation of a second peptide, [des-Gln14]ghrelin with equipotent biological activity [50]. A unique post-translational modification (octanoylation of Ser3, catalysed by ghrelin Ο-acyltransferase (MBOAT4, Q96T53) [134] occurs in both peptides, essential for full activity in binding to ghrelin receptors in the hypothalamus and pituitary, and for the release of growth hormone from the pituitary [59]. Structure activity studies showed the first five N-terminal amino acids to be the minimum required for binding [4], and receptor mutagenesis has indicated overlap of the ghrelin binding site with those for small molecule agonists and allosteric modulators of ghrelin function [45]. An endogenous antagonist and inverse agonist called Liver enriched antimicrobial peptide 2 (Leap2), expressed primarily in hepatocytes and in enterocytes of the proximal intestine [36, 69] inhibits ghrelin receptor-induced GH secretion and food intake [36]. The secretion of Leap2 and ghrelin is inversely regulated under various metabolic conditions [72]. In cell systems, the ghrelin receptor is constitutively active [46], but this is abolished by a naturally occurring mutation (A204E) that results in decreased cell surface receptor expression and is associated with familial short stature [94].","PeriodicalId":14617,"journal":{"name":"IUPHAR/BPS Guide to Pharmacology CITE","volume":"51 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":"135017423","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}
Girolamo Caló, Olivier Civelli, Rainer K. Reinscheid, Chiara Ruzza
{"title":"Neuropeptide S receptor in GtoPdb v.2023.1","authors":"Girolamo Caló, Olivier Civelli, Rainer K. Reinscheid, Chiara Ruzza","doi":"10.2218/gtopdb/f44/2023.1","DOIUrl":"https://doi.org/10.2218/gtopdb/f44/2023.1","url":null,"abstract":"The 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 [71]. Currently, some peptidic and small molecule NPS receptor antagonists are available as research tools [27, 79, 8, 59]. No NPS receptor ligands are currently used clinically.","PeriodicalId":14617,"journal":{"name":"IUPHAR/BPS Guide to Pharmacology CITE","volume":"1 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":"135018438","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}
John P. Adelman, David E. Clapham, Hiroshi Hibino, Atsushi Inanobe, Lily Y. Jan, Andreas Karschin, Yoshihiro Kubo, Yoshihisa Kurachi, Michel Lazdunski, Takashi Miki, Colin G. Nichols, Lawrence G. Palmer, Wade L. Pearson, Henry Sackin, Susumu Seino, Paul A. Slesinger, Stephen Tucker, Carol A. Vandenberg
{"title":"Inwardly rectifying potassium channels (K<sub>IR</sub>) in GtoPdb v.2023.1","authors":"John P. Adelman, David E. Clapham, Hiroshi Hibino, Atsushi Inanobe, Lily Y. Jan, Andreas Karschin, Yoshihiro Kubo, Yoshihisa Kurachi, Michel Lazdunski, Takashi Miki, Colin G. Nichols, Lawrence G. Palmer, Wade L. Pearson, Henry Sackin, Susumu Seino, Paul A. Slesinger, Stephen Tucker, Carol A. Vandenberg","doi":"10.2218/gtopdb/f74/2023.1","DOIUrl":"https://doi.org/10.2218/gtopdb/f74/2023.1","url":null,"abstract":"The 2TM domain family of K channels are also known as the inward-rectifier K channel family. This family includes the strong inward-rectifier K channels (Kir2.x) that are constitutively active, the G-protein-activated inward-rectifier K channels (Kir3.x) and the ATP-sensitive K channels (Kir6.x, which combine with sulphonylurea receptors (SUR1-3)). The pore-forming α subunits form tetramers, and heteromeric channels may be formed within subfamilies (e.g. Kir3.2 with Kir3.3).","PeriodicalId":14617,"journal":{"name":"IUPHAR/BPS Guide to Pharmacology CITE","volume":"58 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":"135018451","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}
Khaled A. Al‐Hosaini, S. Bloom, J. Hedrick, A. Howard, P. Jethwa, S. Luckman, R. Raddatz, N. Semjonous, G. Willars
{"title":"Neuromedin U receptors in GtoPdb v.2023.1","authors":"Khaled A. Al‐Hosaini, S. Bloom, J. Hedrick, A. Howard, P. Jethwa, S. Luckman, R. Raddatz, N. Semjonous, G. Willars","doi":"10.2218/gtopdb/f42/2023.1","DOIUrl":"https://doi.org/10.2218/gtopdb/f42/2023.1","url":null,"abstract":"Neuromedin U receptors (provisional nomenclature as recommended by NC-IUPHAR [30]) are activated by the endogenous 25 amino acid peptide neuromedin U (neuromedin U-25, NmU-25), a peptide originally isolated from pig spinal cord [92]. In humans, NmU-25 appears to be the sole product of a precursor gene (NMU, P48645) showing a broad tissue distribution, but which is expressed at highest levels in the upper gastrointestinal tract, CNS, bone marrow and fetal liver. Much shorter versions of NmU are found in some species, but not in human, and are derived at least in some instances from the proteolytic cleavage of the longer NmU. Despite species differences in NmU structure, the C-terminal region (particularly the C-terminal pentapeptide) is highly conserved and contains biological activity. Neuromedin S (neuromedin S-33) has also been identified as an endogenous agonist [97]. NmS-33 is, as its name suggests, a 33 amino-acid product of a precursor protein derived from a single gene and contains an amidated C-terminal heptapeptide identical to NmU. NmS-33 appears to activate NMU receptors with equivalent potency to NmU-25.","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":"76711020","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":"G protein-coupled estrogen receptor in GtoPdb v.2023.1","authors":"E. Filardo, E. Prossnitz","doi":"10.2218/gtopdb/f22/2023.1","DOIUrl":"https://doi.org/10.2218/gtopdb/f22/2023.1","url":null,"abstract":"The G protein-coupled estrogen receptor (GPER, nomenclature as agreed by the NC-IUPHAR Subcommittee on the G protein-coupled estrogen receptor [26]) was identified following observations of estrogen-evoked cyclic AMP signalling in breast cancer cells [2], which mirrored the differential expression of an orphan 7-transmembrane receptor GPR30 [6]. There are observations of both cell-surface and intracellular expression of the GPER receptor [29, 34]. Selective agonist/ antagonists for GPER have been characterized [26]. Antagonists of the nuclear estrogen receptor, such as fulvestrant [11], tamoxifen [29, 34] and raloxifene [25], as well as the flavonoid 'phytoestrogens' genistein and quercetin [18], are agonists of GPER. Reviews of GPER pharmacology have been published [26]. The roles of GPER in (patho)physiological systems throughout the body (cardiovascular, metabolic, endocrine, immune, reproductive) and in cancer have also been reviewed [26, 27, 20, 17, 9]. The GPER-selective agonist G-1 is currently in Phase I/II clinical trials for cancer (NCT04130516).","PeriodicalId":14617,"journal":{"name":"IUPHAR/BPS Guide to Pharmacology CITE","volume":"29 4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76927224","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":"Integrins in GtoPdb v.2023.1","authors":"R. Farndale, G. Jarvis","doi":"10.2218/gtopdb/f760/2023.1","DOIUrl":"https://doi.org/10.2218/gtopdb/f760/2023.1","url":null,"abstract":"Integrins are unusual signalling proteins that function to signal both from the extracellular environment into the cell, but also from the cytoplasm to the external of the cell. The intracellular signalling cascades associated with integrin activation focus on protein kinase activities, such as focal adhesion kinase and Src. Based on this association between extracellular signals and intracellular protein kinase activity, we have chosen to include integrins in the 'Catalytic receptors' section of the database until more stringent criteria from NC-IUPHAR allows precise definition of their classification.Integrins are heterodimeric entities, composed of α and β subunits, each 1TM proteins, which bind components of the extracellular matrix or counter-receptors expressed on other cells. One class of integrin contains an inserted domain (I) in its α subunit, and if present (in α1, α2, α10, α11, αD, αE, αL, αM and αX), this I domain contains the ligand binding site. All β subunits possess a similar I-like domain, which has the capacity to bind ligand, often recognising the RGD motif. The presence of an α subunit I domain precludes ligand binding through the β subunit. Integrins provide a link between ligand and the actin cytoskeleton (through typically short intracellular domains). Integrins bind several divalent cations, including a Mg2+ ion in the I or I-like domain that is essential for ligand binding. Other cation binding sites may regulate integrin activity or stabilise the 3D structure. Integrins regulate the activity of particular protein kinases, including focal adhesion kinase and integrin-linked kinase. Cellular activation regulates integrin ligand affinity via inside-out signalling and ligand binding to integrins can regulate cellular activity via outside-in signalling.Several drugs that target integrins are in clinical use including: (1) abciximab (αIIbβ3) for short term prevention of coronary thrombosis, (2) vedolizumab (α4β7) to reduce gastrointestinal inflammation, and (3) natalizumab (α4β1) in some cases of severe multiple sclerosis.","PeriodicalId":14617,"journal":{"name":"IUPHAR/BPS Guide to Pharmacology CITE","volume":"72 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81360268","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":"1F. Retinoic acid-related orphans in GtoPdb v.2023.1","authors":"A. Jetten, Hong Soon Kang, Y. Takeda","doi":"10.2218/gtopdb/f88/2023.1","DOIUrl":"https://doi.org/10.2218/gtopdb/f88/2023.1","url":null,"abstract":"Retinoic acid receptor-related orphan receptors (ROR, nomenclature as agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [11, 3]) have yet to be assigned a definitive endogenous ligand, although RORα may be synthesized with a ‘captured’ agonist such as cholesterol [68, 67].","PeriodicalId":14617,"journal":{"name":"IUPHAR/BPS Guide to Pharmacology CITE","volume":"53 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88811828","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":"ZAC in GtoPdb v.2023.1","authors":"P. Davies, T. Hales, A. Jensen, J. A. Peters","doi":"10.2218/gtopdb/f83/2023.1","DOIUrl":"https://doi.org/10.2218/gtopdb/f83/2023.1","url":null,"abstract":"The zinc-activated channel (ZAC, nomenclature as agreed by the NC-IUPHAR Subcommittee for the Zinc Activated Channel) is a member of the Cys-loop family that includes the nicotinic ACh, 5-HT3, GABAA and strychnine-sensitive glycine receptors [2, 3, 5]. The channel is likely to exist as a homopentamer of 4TM subunits that form an intrinsic cation selective channel equipermeable to Na+, K+ and Cs+, but impermeable to Ca2+ and Mg2+ [5]. ZAC displays constitutive activity that can be blocked by tubocurarine, TTFB and high concentrations of Ca2+ [5]. Although denoted ZAC, the channel is more potently activated by H+ and Cu2+, with greater and lesser efficacy than Zn2+, respectively [5]. Orthologs of the human ZACN gene are present in a wide range of mammalian genomes, but notably not in the mouse or rat genomes. [2, 3].","PeriodicalId":14617,"journal":{"name":"IUPHAR/BPS Guide to Pharmacology CITE","volume":"25 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84386935","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}
Stephen P. H. Alexander, P. Doherty, D. Fairlie, C. Fowler, C. Overall, N. Rawlings, C. Southan, A. Turner
{"title":"Hydrolases in GtoPdb v.2023.1","authors":"Stephen P. H. Alexander, P. Doherty, D. Fairlie, C. Fowler, C. Overall, N. Rawlings, C. Southan, A. Turner","doi":"10.2218/gtopdb/f799/2023.1","DOIUrl":"https://doi.org/10.2218/gtopdb/f799/2023.1","url":null,"abstract":"Listed in this section are hydrolases not accumulated in other parts of the Concise Guide, such as monoacylglycerol lipase and acetylcholinesterase. Pancreatic lipase is the predominant mechanism of fat digestion in the alimentary system; its inhibition is associated with decreased fat absorption. CES1 is present at lower levels in the gut than CES2 (P23141), but predominates in the liver, where it is responsible for the hydrolysis of many aliphatic, aromatic and steroid esters. Hormone-sensitive lipase is also a relatively non-selective esterase associated with steroid ester hydrolysis and triglyceride metabolism, particularly in adipose tissue. Endothelial lipase is secreted from endothelial cells and regulates circulating cholesterol in high density lipoproteins.","PeriodicalId":14617,"journal":{"name":"IUPHAR/BPS Guide to Pharmacology CITE","volume":"10 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86002060","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}
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