IUPHAR/BPS Guide to Pharmacology CITE
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Kisspeptin receptor in GtoPdb v.2023.1
Get PDFThe kisspeptin receptor (nomenclature as agreed by the NC-IUPHAR Subcommittee on the kisspeptin receptor [11]), like neuropeptide FF (NPFF), prolactin-releasing peptide (PrP) and QRFP receptors (provisional nomenclature) responds to endogenous peptides with an arginine-phenylalanine-amide (RFamide) motif. kisspeptin-54 (KP54, originally named metastin), kisspeptin-13 (KP13) and kisspeptin-10 (KP10) are biologically-active peptides cleaved from the KISS1 (Q15726) gene product. Kisspeptins have roles in, for example, cancer metastasis, fertility/puberty regulation and glucose homeostasis
Glycine receptors in GtoPdb v.2023.1
Get PDFThe inhibitory glycine receptor (nomenclature as agreed by the NC-IUPHAR Subcommittee on Glycine Receptors) is a member of the Cys-loop superfamily of transmitter-gated ion channels that includes the GABAA, nicotinic acetylcholine and 5-HT3 receptors and Zn2+- activated channels. The glycine receptor is expressed either as a homo-pentamer of α subunits, or a complex of 4α and 1β subunits [131], that contains an intrinsic anion channel. Four differentially expressed isoforms of the α-subunit (α1-α4) and one variant of the β-subunit (β1, GLRB, P48167) have been identified by genomic and cDNA cloning. Further diversity originates from alternative splicing of the primary gene transcripts for α1 (α1INS and α1del), α2 (α2A and α2B), α3 (α3S and α3L) and β (βΔ7) subunits and by mRNA editing of the α2 and α3 subunit [20, 84, 94]. Both α2 splicing and α3 mRNA editing can produce subunits (i.e., α2B and α3P185L) with enhanced agonist sensitivity. Predominantly, the adult form of the receptor contains α1 (or α3) and β subunits whereas the immature form is mostly composed of only α2 subunits [79]. The α4 subunit is a pseudogene in humans [66]. High resolution molecular structures are available for α1 homomeric, α3 homomeric, and αβ hteromeric receptors in a variety of ligand-induced conformations [19, 129, 19, 48, 49, 50]. As in other Cys-loop receptors, the orthosteric binding site for agonists and the competitive antagonist strychnine is formed at the interfaces between the subunits’ extracellular domains. Inclusion of the β-subunit in the pentameric glycine receptor contributes to agonist binding, reduces single channel conductance and alters pharmacology. The β-subunit also anchors the receptor, via an amphipathic sequence within the large intracellular loop region, to gephyrin. This a cytoskeletal attachment protein that binds to a number of subsynaptic proteins involved in cytoskeletal structure and thus clusters and anchors hetero-oligomeric receptors to the synapse [55, 89]. G protein βγ subunits enhance the open state probability of native and recombinant glycine receptors by association with domains within the large intracellular loop [125, 124]. Intracellular chloride concentration modulates the kinetics of native and recombinant glycine receptors [97]. Intracellular Ca2+ appears to increase native and recombinant glycine receptor affinity, prolonging channel open events, by a mechanism that does not involve phosphorylation [26]. Extracellular Zn2+ potentiates GlyR function at nanomolar concentrations [87]. and causes inhibition at higher micromolar concentrations (17)
GPR18, GPR55 and GPR119 in GtoPdb v.2023.1
Get PDFGPR18, GPR55 and GPR119 (provisional nomenclature), although showing little structural similarity to CB1 and CB2 cannabinoid receptors, respond to endogenous agents analogous to the endogenous cannabinoid ligands, as well as some natural/synthetic cannabinoid receptor ligands [104]. Although there are multiple reports to indicate that GPR18, GPR55 and GPR119 can be activated in vitro by N-arachidonoylglycine, lysophosphatidylinositol and N-oleoylethanolamide, respectively, there is a lack of evidence for activation by these lipid messengers in vivo. As such, therefore, these receptors retain their orphan status
Lysophospholipid (S1P) receptors in GtoPdb v.2023.1
Get PDFSphingosine 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]
ABCA subfamily in GtoPdb v.2023.1
Get PDFTo date, 12 members of the human ABCA subfamily are identified. They share a high degree of sequence conservation and have been mostly related with lipid trafficking in a wide range of body locations. Mutations in some of these genes have been described to cause severe hereditary diseases related with lipid transport, such as fatal surfactant deficiency or harlequin ichthyosis. In addition, most of them are hypothesized to participate in the subcellular sequestration of drugs, thereby being responsible for the resistance of several carcinoma cell lines against drug treatment [1, 2]
P1B P-type ATPases: Cu+-ATPases in GtoPdb v.2023.1
Get PDFCopper-transporting ATPases convey copper ions across cell-surface and intracellular membranes. They consist of eight TM domains and associate with multiple copper chaperone proteins (e.g. ATOX1, O00244)
Haem oxygenase in GtoPdb v.2023.1
Get PDFHaem oxygenase (heme,hydrogen-donor:oxygen oxidoreductase (α-methene-oxidizing, hydroxylating)), E.C. 1.14.99.3, converts heme into biliverdin and carbon monoxide, utilizing NADPH as cofactor
Pattern recognition receptors in GtoPdb v.2023.1
Get PDFPattern Recognition Receptors (PRRs, [110]) (nomenclature as agreed by NC-IUPHAR sub-committee on Pattern Recognition Receptors, [20]) participate in the innate immune response to microbial agents, the stimulation of which leads to activation of intracellular enzymes and regulation of gene transcription. PRRs express multiple leucine-rich regions to bind a range of microbially-derived ligands, termed PAMPs or pathogen-associated molecular patterns or endogenous ligands, termed DAMPS or damage-associated molecular patterns. These include peptides, carbohydrates, peptidoglycans, lipoproteins, lipopolysaccharides, and nucleic acids. PRRs include both cell-surface and intracellular proteins. PRRs may be divided into signalling-associated members, identified here, and endocytic members, the function of which appears to be to recognise particular microbial motifs for subsequent cell attachment, internalisation and destruction. Some are involved in inflammasome formation, and modulation of IL-1β cleavage and secretion, and others in the initiation of the type I interferon response. PRRs included in the Guide To PHARMACOLOGY are:Catalytic PRRs (see links below this overview)Toll-like receptors (TLRs)Nucleotide-binding oligomerization domain, leucine-rich repeat containing receptors (NLRs, also known as NOD (Nucleotide oligomerisation domain)-like receptors)RIG-I-like receptors (RLRs)Caspase 4 and caspase 5 Non-catalytic PRRsAbsent in melanoma (AIM)-like receptors (ALRs)C-type lectin-like receptors (CLRs)Other pattern recognition receptorsAdvanced glycosylation end-product specific receptor (RAGE
Peptidyl-prolyl cis/trans isomerases in GtoPdb v.2023.1
Get PDFPeptidyl-prolyl cis/trans isomerases (PPIases) are an enzyme family which catalyse the cis/trans isomerisation of proline peptide bonds to promote the folding and re-folding of peptides and proteins. Three subfamilies have been identified: cyclophilins, FK506-binding proteins and parvulins. Individual PPIases are overexpressed in a number of cancers [62], and family members have been targetted for immunosuppressant effects
S33: Prolyl aminopeptidase in GtoPdb v.2023.1
Get PDFPeptidase family S33 contains mainly exopeptidases that act at the N-terminus of peptides