IUPHAR/BPS Guide to Pharmacology CITE
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ABCC subfamily in GtoPdb v.2025.3
No full textSubfamily ABCC contains thirteen members and nine of these transporters are referred to as the Multidrug Resistance Proteins (MRPs). The MRP proteins are found throughout nature and they mediate many important functions. They are known to be involved in ion transport, toxin secretion, and signal transduction [7, 2]
Lanosterol biosynthesis pathway in GtoPdb v.2025.3
No full textLanosterol is a precursor for cholesterol, which is synthesized primarily in the liver in a pathway often described as the mevalonate or HMG-CoA reductase pathway. The first two steps (formation of acetoacetyl CoA and the mitochondrial generation of (S)-3-hydroxy-3-methylglutaryl-CoA) are also associated with oxidation of fatty acids
Taste 2 receptors in GtoPdb v.2025.3
No full textTaste 2 receptors or Bitter taste receptors (TAS2Rs) are G protein-coupled receptors expressed in oral sensory cells and a variety of non-gustatory tissues. The ~25 human TAS2Rs share low amino acid sequence identities with other GPCR families and are classified as broadly tuned "generalist" receptors with numerous, chemically diverse bitter agonists, as narrowly tuned "specialist" receptors with very few activators, as intermediately tuned receptors with an average number of agonists, or receptors specialized to interact with chemically defined activators [39]. The number of functional bitter taste receptor genes varies among species and orthologues might not be functionally conserved. Due to their expression in various tissues, the signal transduction of TAS2Rs is complex. Some TAS2Rs interact with drugs such as analgesic, anti-inflammatory, and antibacterial compounds. The specialist database BitterDB contains additional information on bitter compounds and receptors [16]. Recently, several experimental cryo-electron structures of TAS2Rs have been published [43]
Lysophospholipid (S1P) receptors in GtoPdb v.2025.3
No full textSphingosine 1-phosphate (S1P) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Lysophospholipid receptors [98]) are activated by the endogenous lipid sphingosine 1-phosphate (S1P). Originally cloned as orphan members of the endothelial differentiation gene (edg) family [16, 125], the receptors are currently designated as S1P1R through S1P5R [75, 16, 125]. 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, 54]. 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 [103, 105]. The structures of S1P1 [185, 70, 110, 189], S1P2 [32], S1P3[118, 192], and S1P5 [112, 190] are solved, and confirmed aspects of ligand binding, specificity, and receptor activation, determined previously through biochemical and genetic studies [70, 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 and ozanimod target S1P1 and S1P5, while etrasimod targets S1P1, S1P4 and S1P5; and ponesimod targets S1P1 alone, and all are FDA approved for the treatment of various MS forms [16, 125] and/or ulcerative colitis for ozanimod and etrasimod [147, 158]. 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, although most S1P1 effects appear to involve functional antagonism [143, 37, 64, 65]
SLC22 family of organic cation and anion transporters in GtoPdb v.2025.3
No full textThe SLC22 family of transporters is mostly composed of non-selective transporters, which are expressed highly in liver, kidney and intestine, playing a major role in drug disposition. The family may be divided into three subfamilies based on the nature of the substrate transported: organic cations (OCTs), organic anions (OATs) and organic zwiterrion/cations (OCTN). Membrane topology is predicted to contain 12 TM domains with intracellular termini, and an extended extracellular loop at TM 1/2
SLC1 family of amino acid transporters in GtoPdb v.2025.3
No full textThe SLC1 family of sodium dependent transporters includes the plasma membrane located glutamate transporters and the neutral amino acid transporters ASCT1 and ASCT2 [3, 54, 40, 41, 9]
CFTR in GtoPdb v.2025.3
No full textCFTR is a member of the ABC transporter superfamily, but, uniquely, it is an ion channel, allowing electrodiffusion of Cl- and HCO3-. It is activated by phosphorylation, mainly by PKA on its regulatory domain (R domain). Conserved nucleotide binding domains (NBD1 and NBD2) couple ATP binding and hydrolysis to gate opening and closing, respectively [8]. CFTR is expressed apically in polarized epithelial cells in various organs where it controls volume and pH of fluid secretions as well as mucin unfolding and release [26]. CFTR transcripts are present in secretory and ionocyte cells in airway epithelia [29, 33], crypt enterocytes, goblet and CFTR-high expressing cells in the intestine [5, 3], pancreatic duct cells [13], intra- and extra-hepatic cholangiocytes 33318612 [48] and others. Mutations in the CFTR gene cause the genetic disease cystic fibrosis (CF) [38]. The most common mutation, F508del, is present in at least one gene copy in ~80% of patients worldwide, but there are ~1000 different variants known to cause CF. Mutations affect CFTR biogenesis (folding, maturation, trafficking, metabolic stability) and/or ion-channel function. Vertex Pharmaceuticals developed small-molecule CFTR modulator drugs that improve biogenesis ("correctors") or open probability ("potentiators") of defective CFTR variants. Triple combination therapies, including two correctors and one potentiator (e.g. Trikafta®: elexacaftor, tezacaftor, ivacaftor), are standard of care for patients carrying at least one copy of the F508del variant. Patients carrying mutations only affecting ion-channel function ("gating mutations" e.g. G551D) are treated with ivacaftor (potentiator) alone. Cryo-EM structures of Trikafta-bound F508del-E1371Q-CFTR reveal that all three compounds bind at the protein-membrane interface, in shallow pockets on CFTR\u27s surface [14]. While low/absent CFTR activity causes CF, over-activation of CFTR (due to bacterial toxins such as cholera toxin) results in secretory diarrhoeas, causing large intestinal loss of fluid and alkali [11]. No inhibitors have been approved yet for emergency treatment of secretory diarrhoeas
SLC8 family of sodium/calcium exchangers in GtoPdb v.2025.3
No full textThe sodium/calcium exchangers (NCX) use the extracellular sodium concentration to facilitate the extrusion of calcium out of the cell. Alongside the plasma membrane Ca2+-ATPase (PMCA) and sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA), as well as the sodium/potassium/calcium exchangers (NKCX, SLC24 family), NCX allow recovery of intracellular calcium back to basal levels after cellular stimulation. When intracellular sodium ion levels rise, for example, following depolarisation, these transporters can operate in the reverse direction to allow calcium influx and sodium efflux, as an electrogenic mechanism. Structural modelling suggests the presence of 9 TM segments, with a large intracellular loop between the fifth and sixth TM segments [1]
Chemerin receptors in GtoPdb v.2025.3
No full textNomenclature for the chemerin receptors is presented as recommended by NC-IUPHAR [15, 44]). The chemoattractant protein and adipokine, chemerin, has been shown to be the endogenous ligand for both chemerin family receptors. Chemerin1 was the founding family member, and when GPR1 was de-orphanised it was re-named Chermerin2 [44]. Chemerin1 is also activated by the lipid-derived, anti-inflammatory ligand resolvin E1 (RvE1), which is formed via the sequential metabolism of EPA by aspirin-modified cyclooxygenase and lipoxygenase [2, 3]. In addition, two GPCRs for resolvin D1 (RvD1) have been identified: FPR2/ALX, the lipoxin A4 receptor, and GPR32, an orphan receptor [47]
GPR18, GPR55 and GPR119 in GtoPdb v.2025.3
No full textGPR18, 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 [105]. 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