IUPHAR/BPS Guide to Pharmacology CITE
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Chemerin receptors in GtoPdb v.2021.3
Get PDFNomenclature for the chemerin receptors is presented as recommended by NC-IUPHAR [15, 43]). 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 [43]. 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 [45]
Phosphatidylinositol kinases in GtoPdb v.2021.3
Get PDFPhosphatidylinositol may be phosphorylated at either 3- or 4- positions on the inositol ring by PI 3-kinases or PI 4-kinases, respectively.Phosphatidylinositol 3-kinasesPhosphatidylinositol 3-kinases (PI3K, provisional nomenclature) catalyse the introduction of a phosphate into the 3-position of phosphatidylinositol (PI), phosphatidylinositol 4-phosphate (PIP) or phosphatidylinositol 4,5-bisphosphate (PIP2). There is evidence that PI3K can also phosphorylate serine/threonine residues on proteins. In addition to the classes described below, further serine/threonine protein kinases, including ATM (Q13315) and mTOR (P42345), have been described to phosphorylate phosphatidylinositol and have been termed PI3K-related kinases. Structurally, PI3Ks have common motifs of at least one C2, calcium-binding domain and helical domains, alongside structurally-conserved catalytic domains. wortmannin and LY 294002 are widely-used inhibitors of PI3K activities. wortmannin is irreversible and shows modest selectivity between Class I and Class II PI3K, while LY294002 is reversible and selective for Class I compared to Class II PI3K.Class I PI3Ks (EC 2.7.1.153) phosphorylate phosphatidylinositol 4,5-bisphosphate to generate phosphatidylinositol 3,4,5-trisphosphate and are heterodimeric, matching catalytic and regulatory subunits. Class IA PI3Ks include p110α, p110β and p110δ catalytic subunits, with predominantly p85 and p55 regulatory subunits. The single catalytic subunit that forms Class IB PI3K is p110γ. Class IA PI3Ks are more associated with receptor tyrosine kinase pathways, while the Class IB PI3K is linked more with GPCR signalling.Class II PI3Ks (EC 2.7.1.154) phosphorylate phosphatidylinositol to generate phosphatidylinositol 3-phosphate (and possibly phosphatidylinositol 4-phosphate to generate phosphatidylinositol 3,4-bisphosphate). Three monomeric members exist, PI3K-C2α, β and β, and include Ras-binding, Phox homology and two C2 domains.The only class III PI3K isoform (EC 2.7.1.137) is a heterodimer formed of a catalytic subunit (VPS34) and regulatory subunit (VPS15).Phosphatidylinositol 4-kinasesPhosphatidylinositol 4-kinases (EC 2.7.1.67) generate phosphatidylinositol 4-phosphate and may be divided into higher molecular weight type III and lower molecular weight type II forms
Galanin receptors in GtoPdb v.2021.3
Get PDFGalanin receptors (provisional nomenclature as recommended by NC-IUPHAR [57]) are activated by the endogenous peptides galanin and galanin-like peptide. Human galanin is a 30 amino-acid non-amidated peptide [52]; in other species, it is 29 amino acids long and C-terminally amidated. Amino acids 1-14 of galanin are highly conserved in mammals, birds, reptiles, amphibia and fish. Shorter peptide species (e.g. human galanin-1-19 [21] and porcine galanin-5-29 [170]) and N-terminally extended forms (e.g. N-terminally seven and nine residue elongated forms of porcine galanin [22, 170]) have been reported. More recently, the newly-identified peptide, spexin (SPX), has been reported to activate human GAL2 and GAL3 (but not GAL1) receptors in heterologous expression systems; and to alter GAL2/3 receptor-related behaviours in animals [89]
Histamine receptors in GtoPdb v.2021.3
Get PDFHistamine receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Histamine Receptors [80, 173]) are activated by the endogenous ligand histamine. Marked species differences exist between histamine receptor orthologues [80]. The human and rat H3 receptor genes are subject to significant splice variance [12]. The potency order of histamine at histamine receptor subtypes is H3 = H4 > H2 > H1 [173]. Some agonists at the human H3 receptor display significant ligand bias [182]. Antagonists of all 4 histamine receptors have clinical uses: H1 antagonists for allergies (e.g. cetirizine), H2 antagonists for acid-reflux diseases (e.g. ranitidine), H3 antagonists for narcolepsy (e.g. pitolisant/WAKIX; Registered) and H4 antagonists for atopic dermatitis (e.g. adriforant; Phase IIa) [173] and vestibular neuritis (AUV) (SENS-111 (Seliforant, previously UR-63325), entered and completed vestibular neuritis (AUV) Phase IIa efficacy and safety trials, respectively) [216, 8]
Melanocortin receptors in GtoPdb v.2021.3
Get PDFMelanocortin receptors (provisional nomenclature as recommended by NC-IUPHAR [41]) are activated by members of the melanocortin family (α-MSH, β-MSH and γ-MSH forms; δ form is not found in mammals) and adrenocorticotrophin (ACTH). Endogenous antagonists include agouti and agouti-related protein. ACTH(1-24) was approved by the US FDA as a diagnostic agent for adrenal function test, whilst NDP-MSH was approved by EMA for the treatment of erythropoietic protoporphyria. Several synthetic melanocortin receptor agonists are under clinical development
GABAA receptors in GtoPdb v.2021.3
Get PDFThe GABAA receptor is a ligand-gated ion channel of the Cys-loop family that includes the nicotinic acetylcholine, 5-HT3 and strychnine-sensitive glycine receptors. GABAA receptor-mediated inhibition within the CNS occurs by fast synaptic transmission, sustained tonic inhibition and temporally intermediate events that have been termed \u27GABAA, slow\u27 [45]. GABAA receptors exist as pentamers of 4TM subunits that form an intrinsic anion selective channel. Sequences of six α, three β, three γ, one δ, three ρ, one ε, one π and one θ GABAA receptor subunits have been reported in mammals [278, 235, 236, 283]. The π-subunit is restricted to reproductive tissue. Alternatively spliced versions of many subunits exist (e.g. α4- and α6- (both not functional) α5-, β2-, β3- and γ2), along with RNA editing of the α3 subunit [71]. The three ρ-subunits, (ρ1-3) function as either homo- or hetero-oligomeric assemblies [359, 50]. Receptors formed from ρ-subunits, because of their distinctive pharmacology that includes insensitivity to bicuculline, benzodiazepines and barbiturates, have sometimes been termed GABAC receptors [359], but they are classified as GABAA receptors by NC-IUPHAR on the basis of structural and functional criteria [16, 235, 236].Many GABAA receptor subtypes contain α-, β- and γ-subunits with the likely stoichiometry 2α.2β.1γ [168, 235]. It is thought that the majority of GABAA receptors harbour a single type of α- and β -subunit variant. The α1β2γ2 hetero-oligomer constitutes the largest population of GABAA receptors in the CNS, followed by the α2β3γ2 and α3β3γ2 isoforms. Receptors that incorporate the α4- α5-or α6-subunit, or the β1-, γ1-, γ3-, δ-, ε- and θ-subunits, are less numerous, but they may nonetheless serve important functions. For example, extrasynaptically located receptors that contain α6- and δ-subunits in cerebellar granule cells, or an α4- and δ-subunit in dentate gyrus granule cells and thalamic neurones, mediate a tonic current that is important for neuronal excitability in response to ambient concentrations of GABA [209, 272, 83, 19, 288]. GABA binding occurs at the β+/α- subunit interface and the homologous γ+/α- subunits interface creates the benzodiazepine site. A second site for benzodiazepine binding has recently been postulated to occur at the α+/β- interface ([254]; reviewed by [282]). The particular α-and γ-subunit isoforms exhibit marked effects on recognition and/or efficacy at the benzodiazepine site. Thus, receptors incorporating either α4- or α6-subunits are not recognised by ‘classical’ benzodiazepines, such as flunitrazepam (but see [356]). The trafficking, cell surface expression, internalisation and function of GABAA receptors and their subunits are discussed in detail in several recent reviews [52, 140, 188, 316] but one point worthy of note is that receptors incorporating the γ2 subunit (except when associated with α5) cluster at the postsynaptic membrane (but may distribute dynamically between synaptic and extrasynaptic locations), whereas as those incorporating the δ subunit appear to be exclusively extrasynaptic. NC-IUPHAR [16, 235, 3, 2] class the GABAA receptors according to their subunit structure, pharmacology and receptor function. Currently, eleven native GABAA receptors are classed as conclusively identified (i.e., α1β2γ2, α1βγ2, α3βγ2, α4βγ2, α4β2δ, α4β3δ, α5βγ2, α6βγ2, α6β2δ, α6β3δ and ρ) with further receptor isoforms occurring with high probability, or only tentatively [235, 236]. It is beyond the scope of this Guide to discuss the pharmacology of individual GABAA receptor isoforms in detail; such information can be gleaned in the reviews [16, 95, 168, 173, 143, 278, 216, 235, 236] and [9, 10]. Agents that discriminate between α-subunit isoforms are noted in the table and additional agents that demonstrate selectivity between receptor isoforms, for example via β-subunit selectivity, are indicated in the text below. The distinctive agonist and antagonist pharmacology of ρ receptors is summarised in the table and additional aspects are reviewed in [359, 50, 145, 223].Several high-resolution cryo-electron microscopy structures have been described in which the full-length human α1β3γ2L GABAA receptor in lipid nanodiscs is bound to the channel-blocker picrotoxin, the competitive antagonist bicuculline, the agonist GABA (γ-aminobutyric acid), and the classical benzodiazepines alprazolam and diazepam [198]
3A. Estrogen receptors in GtoPdb v.2021.3
Get PDFEstrogen receptor (ER) activity regulates diverse physiological processes via transcriptional modulation of target genes [1]. 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
SLC28 and SLC29 families of nucleoside transporters in GtoPdb v.2021.3
Get PDFNucleoside transporters are divided into two families, the sodium-dependent, concentrative solute carrier family 28 (SLC28) and the equilibrative, solute carrier family 29 (SLC29). The endogenous substrates are typically nucleosides, although some family members can also transport nucleobases and organic cations [1]
SLC15 family of peptide transporters in GtoPdb v.2021.3
Get PDFThe Solute Carrier 15 (SLC15) family of peptide transporters, alias H+-coupled oligopeptide cotransporter family, is a group of membrane transporters known for their key role in the cellular uptake of di- and tripeptides (di/tripeptides). Of its members, SLC15A1 (PEPT1) chiefly mediates intestinal absorption of luminal di/tripeptides from overall dietary protein digestion, SLC15A2 (PEPT2) mainly allows renal tubular reuptake of di/tripeptides from ultrafiltration and brain-to-blood efflux of di/tripeptides in the choroid plexus, SLC15A3 (PHT2) and SLC15A4 (PHT1) interact with both di/tripeptides and histidine, e.g. in certain immune cells, and SLC15A5 has unknown physiological function. In addition, the SLC15 family of peptide transporters variably interacts with a very large number of peptidomimetics and peptide-like drugs. It is conceivable, based on the currently acknowledged structural and functional differences, to divide the SLC15 family of peptide transporters into two subfamilies [3]
Tumour necrosis factor (TNF) receptor family in GtoPdb v.2021.3
Get PDFDysregulated TNFR signalling is associated with many inflammatory disorders, including some forms of arthritis and inflammatory bowel disease, and targeting TNF has been an effective therapeutic strategy in these diseases and for cancer immunotherapy [5, 6, 49]