IUPHAR/BPS Guide to Pharmacology CITE
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Adenosine receptors in GtoPdb v.2021.2
Get PDFAdenosine receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Adenosine Receptors [110]) are activated by the endogenous ligand adenosine (potentially inosine also at A3 receptors). Crystal structures for the antagonist-bound [153, 313, 221, 61], agonist-bound [375, 203, 204] and G protein-bound A2A adenosine receptors [49] have been described. The structures of an antagonist-bound A1 receptor [128] and an adenosine-bound A1 receptor-Gi complex [86] have been resolved by cryo-electronmicroscopy. Another structure of an antagonist-bound A1 receptor obtained with X-ray crystallography has also been reported [57]. caffeine is a nonselective antagonist for adenosine receptors, while istradefylline, a selective A2A receptor antagonist, is on the market for the treatment of Parkinson\u27s disease
Motilin receptor in GtoPdb v.2021.2
Get PDFMotilin receptors (provisional nomenclature) are activated by motilin, a 22 amino-acid peptide derived from a precursor (MLN, P12872), which may also generate a motilin-associated peptide. There are significant species differences in the structure of motilin and its receptor. In humans and large mammals such as dog, activation of these receptors by motilin released from endocrine cells in the duodenal mucosa during fasting, induces propulsive phase III movements. This activity is associated with promoting hunger in humans. Drugs and other non-peptide compounds which activate the motilin receptor may generate a more long-lasting ability to increase cholinergic activity within the upper gut, to promote gastrointestinal motility; this activity is suggested to be responsible for the gastrointestinal prokinetic effects of certain macrolide antibiotics (often called motilides; e.g. erythromycin, azithromycin), although for many of these molecules the evidence is sparse. Relatively high doses may induce vomiting and in humans, nausea
Cytochrome P450 in GtoPdb v.2021.2
Get PDFThe 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
G protein-coupled estrogen receptor in GtoPdb v.2021.3
Get PDFThe G protein-coupled estrogen receptor (GPER, nomenclature as agreed by the NC-IUPHAR Subcommittee on the G protein-coupled estrogen receptor [25]) 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 [28, 33]. Selective agonist/ antagonists for GPER have been characterized [25]. Antagonists of the nuclear estrogen receptor, such as fulvestrant [11], tamoxifen [28, 33] and raloxifene [24], as well as the flavonoid \u27phytoestrogens\u27 genistein and quercetin [17], are agonists of GPER. A complete review of GPER pharmacology has been published [25]. The roles of GPER in physiological systems throughout the body (cardiovascular, metabolic, endocrine, immune, reproductive) and in cancer have also been reviewed [25, 26, 19, 16, 9]. The GPER-selective agonist G-1 is currently in Phase I/II clinical trials for cancer (NCT04130516)
5-HT3 receptors in GtoPdb v.2021.3
Get PDFThe 5-HT3 receptor (nomenclature as agreed by the NC-IUPHAR Subcommittee on 5-Hydroxytryptamine (serotonin) receptors [69]) 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]. 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 [86, 125], 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 [127, 66, 161]. 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 [161]. The co-expression of 5-HT3A and 5-HT3C-E subunits has been demonstrated in human colon [85]. 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 [99, 154]. The 5-HT3B subunit imparts distinctive biophysical properties upon hetero-oligomeric 5-HT3AB versus homo-oligomeric 5-HT3A recombinant receptors [35, 44, 59, 88, 143, 132, 82], 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 [44, 33, 38]) which may be explained by the orthosteric binding site residing at an interface formed between 5-HT3A subunits [99, 154]. However, 5-HT3A and 5-HT3AB receptors differ in their allosteric regulation by some general anaesthetic agents, small alcohols and indoles [142, 139, 73]. The potential diversity of 5-HT3 receptors is increased by alternative splicing of the genes HTR3A and HTR3E [67, 21, 127, 126, 123]. 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 [156, 82, 123]. To date, inclusion of the 5-HT3A subunit appears imperative for 5-HT3 receptor function
SLC23 family of ascorbic acid transporters in GtoPdb v.2021.3
Get PDFPredicted to be 12 TM segment proteins, members of this family transport the reduced form of ascorbic acid (while the oxidized form may be handled by members of the SLC2 family (GLUT1/SLC2A1, GLUT3/SLC2A3 and GLUT4/SLC2A4). phloretin is considered a non-selective inhibitor of these transporters, with an affinity in the micromolar range [1]
Adenosine turnover in GtoPdb v.2021.3
Get PDFA 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)
Prokineticin receptors (version 2020.4) in the IUPHAR/BPS Guide to Pharmacology Database
Get PDFProkineticin receptors, PKR1 and PKR2 (provisional nomenclature as recommended by NC-IUPHAR [23]) 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, [65]) is a potent, non-selective agonist at prokineticin receptors [41], while Bv8, an orthologue of PROK2 from amphibians (Bombina sp., [44]), is equipotent at recombinant PKR1 and PKR2 [48], and has high potency in macrophage chemotaxis assays, which are lost in PKR1-null mice
SARS-CoV-2 proteins (version 2020.2) in the IUPHAR/BPS Guide to Pharmacology Database
Get PDFCoronaviruses are large, often spherical, enveloped, single-stranded positive-sense RNA viruses, ranging in size from 80-220 nm. Of the four structural proteins encoded in the viral genome, the RNA winds around the highly basic nucleocapsid (N) protein. The three other structural proteins, envelope (E), membrane (M) and spike (S), are transmembrane proteins. The E protein is a small (9-12 kDa) single transmembrane domain protein, which enables virus assembly with the M protein, a larger (23-35 kDa) 3TM protein. Coronaviruses are named for the crown-shaped appearance of the virus due to the large (120+ kDa) S spike 1TM glycoprotein, which forms extended homotrimers. The spike protein binds to the animal host cell by interacting with specific anchoring proteins, typically proteinases, such as angiotensin-converting enzyme 2 or aminopeptidase N. This binding facilitates viral entry into the cell and the release of the genome. Aside from the four structural proteins, the remainder of the genome encodes accessory or non-structural proteins and includes proteinases to cleave the two encoded polyproteins. The remainder of the genome encodes elements for viral replication, assembly and release, as well as proteins which manipulate the host\u27s innate immune system
Delta subfamily (version 2020.4) in the IUPHAR/BPS Guide to Pharmacology Database
Get PDFPKCδ and PKCθ are PKC isoforms that are activated by diacylglycerol and may be inhibited by calphostin C, Gö 6983 and chelerythrine