IUPHAR/BPS Guide to Pharmacology CITE
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Neuropeptide Y receptors in GtoPdb v.2023.1
Get PDFNeuropeptide Y (NPY) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Neuropeptide Y Receptors [158]) are activated by the endogenous peptides neuropeptide Y, neuropeptide Y-(3-36), peptide YY, PYY-(3-36) and pancreatic polypeptide (PP). The receptor originally identified as the Y3 receptor has been identified as the CXCR4 chemokine recepter (originally named LESTR, [139]). The y6 receptor is a functional gene product in mouse, absent in rat, but contains a frame-shift mutation in primates producing a truncated non-functional gene [84]. Three-dimensional structures have been determined for subtype active receptors Y1, Y2 and Y4 [211, 114] and inactive antagonist bound Y1 and Y2 receptors [240, 210]. Many of the agonists exhibit differing degrees of selectivity dependent on the species examined. For example, the potency of PP is greater at the rat Y4 receptor than at the human receptor [62]. In addition, many agonists lack selectivity for individual subtypes, but can exhibit comparable potency against pairs of NPY receptor subtypes, or have not been examined for activity at all subtypes. [125I]-PYY or [125I]-NPY can be used to label Y1, Y2, Y5 and y6 subtypes non-selectively, while [125I][cPP(1-7), NPY(19-23), Ala31, Aib32, Gln34]hPP may be used to label Y5 receptors preferentially (note that cPP denotes chicken peptide sequence and hPP is the human sequence)
Thyrotropin-releasing hormone receptors in GtoPdb v.2023.1
Get PDFThyrotropin-releasing hormone (TRH) receptors (provisional nomenclature as recommended by NC-IUPHAR [14]) are activated by the endogenous tripeptide TRH (pGlu-His-ProNH2). TRH and TRH analogues fail to distinguish TRH1 and TRH2 receptors [29]. [3H]TRH (human, mouse, rat) is able to label both TRH1 and TRH2 receptors with Kd values of 13 and 9 nM respectively. Synthesis and biology of ring-modified L-Histidine containing TRH analogues has been reported [23]
Ionotropic glutamate receptors in GtoPdb v.2023.1
Get PDFThe ionotropic glutamate receptors comprise members of the NMDA (N-methyl-D-aspartate), AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid) and kainate receptor classes, named originally according to their preferred, synthetic, agonist [36, 94, 157]. Receptor heterogeneity within each class arises from the homo-oligomeric, or hetero-oligomeric, assembly of distinct subunits into cation-selective tetramers. Each subunit of the tetrameric complex comprises an extracellular amino terminal domain (ATD), an extracellular ligand binding domain (LBD), 3 TM domains (M1, M3 and M4), a channel lining re-entrant \u27p-loop\u27 (M2) located between M1 and M3 and an intracellular carboxy- terminal domain (CTD) [101, 70, 109, 157, 84]. The X-ray structure of a homomeric ionotropic glutamate receptor (GluA2- see below) has recently been solved at 3.6Å resolution [145] and although providing the most complete structural information current available may not representative of the subunit arrangement of, for example, the heteromeric NMDA receptors [73]. It is beyond the scope of this supplement to discuss the pharmacology of individual ionotropic glutamate receptor isoforms in detail; such information can be gleaned from [36, 68, 32, 79, 43, 116, 25, 67, 157, 114, 115, 165]. Agents that discriminate between subunit isoforms are, where appropriate, noted in the tables and additional compounds that distinguish between receptor isoforms are indicated in the text below.The classification of glutamate receptor subunits has been re-addressed by NC-IUPHAR [29]. The scheme developed recommends a nomenclature for ionotropic glutamate receptor subunits that is adopted here.NMDA receptorsNMDA receptors assemble as obligate heteromers that may be drawn from GluN1, GluN2A, GluN2B, GluN2C, GluN2D, GluN3A and GluN3B subunits. Alternative splicing can generate eight isoforms of GluN1 with differing pharmacological properties. Various splice variants of GluN2B, 2C, 2D and GluN3A have also been reported. Activation of NMDA receptors containing GluN1 and GluN2 subunits requires the binding of two agonists, glutamate to the S1 and S2 regions of the GluN2 subunit and glycine to S1 and S2 regions of the GluN1 subunit [42, 26]. The minimal requirement for efficient functional expression of NMDA receptors in vitro is a di-heteromeric assembly of GluN1 and at least one GluN2 subunit variant, as a dimer of heterodimers arrangement in the extracellular domain [49, 101, 73]. However, more complex tri-heteromeric assemblies, incorporating multiple subtypes of GluN2 subunit, or GluN3 subunits, can be generated in vitro and occur in vivo. The NMDA receptor channel commonly has a high relative permeability to Ca2+ and is blocked, in a voltage-dependent manner, by Mg2+ such that at resting potentials the response is substantially inhibited.AMPA and Kainate receptorsAMPA receptors assemble as homomers, or heteromers, that may be drawn from GluA1, GluA2, GluA3 and GluA4 subunits. Transmembrane AMPA receptor regulatory proteins (TARPs) of class I (i.e. γ2, γ3, γ4 and γ8) act, with variable stoichiometry, as auxiliary subunits to AMPA receptors and influence their trafficking, single channel conductance gating and pharmacology (reviewed in [44, 105, 155, 66]). Functional kainate receptors can be expressed as homomers of GluK1, GluK2 or GluK3 subunits. GluK1-3 subunits are also capable of assembling into heterotetramers (e.g. GluK1/K2; [89, 121, 120]). Two additional kainate receptor subunits, GluK4 and GluK5, when expressed individually, form high affinity binding sites for kainate, but lack function, but can form heteromers when expressed with GluK1-3 subunits (e.g. GluK2/K5; reviewed in [121, 67, 120]). Kainate receptors may also exhibit \u27metabotropic\u27 functions [89, 133]. As found for AMPA receptors, kainate receptors are modulated by auxiliary subunits (Neto proteins, [120, 90]). An important function difference between AMPA and kainate receptors is that the latter require extracellular Na+ and Cl- for their activation [12, 122]. RNA encoding the GluA2 subunit undergoes extensive RNA editing in which the codon encoding a p-loop glutamine residue (Q) is converted to one encoding arginine (R). This Q/R site strongly influences the biophysical properties of the receptor. Recombinant AMPA receptors lacking RNA edited GluA2 subunits are: (1) permeable to Ca2+; (2) blocked by intracellular polyamines at depolarized potentials causing inward rectification (the latter being reduced by TARPs); (3) blocked by extracellular argiotoxin and joro spider toxins and (4) demonstrate higher channel conductances than receptors containing the edited form of GluA2 [141, 65]. GluK1 and GluK2, but not other kainate receptor subunits, are similarly edited and broadly similar functional characteristics apply to kainate receptors lacking either an RNA edited GluK1, or GluK2, subunit [89, 120]. Native AMPA and kainate receptors displaying differential channel conductances, Ca2+ permeabilites and sensitivity to block by intracellular polyamines have been identified [31, 65, 93]. GluA1-4 can exist as two variants generated by alternative splicing (termed ‘flip’ and ‘flop’) that differ in their desensitization kinetics and their desensitization in the presence of cyclothiazide which stabilises the nondesensitized state. TARPs also stabilise the non-desensitized conformation of AMPA receptors and facilitate the action of cyclothiazide [105]. Splice variants of GluK1-3 also exist which affects their trafficking [89, 120]
Acid-sensing (proton-gated) ion channels (ASICs) in GtoPdb v.2023.1
Get PDFAcid-sensing ion channels (ASICs, nomenclature as agreed by NC-IUPHAR [48, 2, 3]) are members of a Na+ channel superfamily that includes the epithelial Na+ channel (ENaC), the FMRF-amide activated channel (FaNaC) of invertebrates, the degenerins (DEG) of Caenorhabitis elegans, channels in Drosophila melanogaster and \u27orphan\u27 channels that include BLINaC [70] and INaC [72] that have also been named BASICs, for bile acid-activated ion channels [90]. ASIC subunits contain 2 TM domains and assemble as homo- or hetero-trimers [45, 41, 7, 94, 93, 77] to form proton-gated, voltage-insensitive, Na+ permeable, channels that are activated by levels of acidosis occurring in both physiological and pathophysiological conditions with ASIC3 also playing a role in mechanosensation (reviewed in [44, 89, 48, 69, 23]). Splice variants of ASIC1 [termed ASIC1a (ASIC, ASICα, BNaC2α) [84], ASIC1b (ASICβ, BNaC2β) [19] and ASIC1b2 (ASICβ2) [79]; note that ASIC1a is also permeable to Ca2+], ASIC2 [termed ASIC2a (MDEG1, BNaC1α, BNC1α) [66, 85, 40] and ASIC2b (MDEG2, BNaC1β) [56]] differ in the first third of the protein. Unlike ASIC2a (listed in table), heterologous expression of ASIC2b alone does not support H+-gated currents. A third member, ASIC3 (DRASIC, TNaC1) [83] is one of the most pH-sensitive isoforms (along with ASIC1a) and has the fastest activation and desensitisation kinetics, however can also carry small sustained currents. ASIC4 (SPASIC) evolved as a proton-sensitive channel but seems to have lost this function in mammals [58]. Mammalian ASIC4 does not support a proton-gated channel in heterologous expression systems but is reported to downregulate the expression of ASIC1a and ASIC3 [1, 43, 34, 54]. ASICs channels are primarily expressed in central (ASIC1a, -2a, 2b and -4) and peripheral neurons including nociceptors (ASIC1-3) where they participate in neuronal sensitivity to acidosis. Humans express, in contrast to rodents, ASIC3 also in the brain [27]. ASICs have also been detected in taste receptor cells (ASIC1-3)), photoreceptors and retinal cells (ASIC1-3), cochlear hair cells (ASIC1b), testis (hASIC3), pituitary gland (ASIC4), lung epithelial cells (ASIC1a and -3), urothelial cells, adipose cells (ASIC3), vascular smooth muscle cells (ASIC1-3), immune cells (ASIC1,-3 and -4) and bone (ASIC1-3) (ASIC distribution is reviewed in [55, 28, 42]). A neurotransmitter-like function of protons has been suggested, involving postsynaptically located ASICs of the CNS in functions such as learning and fear perception [35, 50, 97], responses to focal ischemia [91] and to axonal degeneration in autoimmune inflammation in a mouse model of multiple sclerosis [39], as well as seizures [98] and pain [89, 29, 30, 13, 32]. Heterologously expressed heteromultimers form ion channels with differences in kinetics, ion selectivity, pH- sensitivity and sensitivity to blockers that resemble some of the native proton activated currents recorded from neurones [56, 5, 38, 11]. In general, the known small molecule inhibitors of ASICs are non-selective or partially selective, whereas the venom peptide inhibitors have substantially higher selectivity and potency. Several clinically used drugs are known to inhibit ASICs, however they are generally more potent at other targets (e.g. amiloride at ENaCs, ibuprofen at COX enzymes) [68, 63]. The information in the tables below are for the effects of inhibitors on homomeric channels, for information of known effects on heteromeric channels see the comments below
SLC31 family of copper transporters in GtoPdb v.2023.1
Get PDFSLC31 family members, alongside the Cu-ATPases are involved in the regulation of cellular copper levels. The CTR1 transporter is a cell-surface transporter to allow monovalent copper accumulation into cells, while CTR2 appears to be a vacuolar/vesicular transporter [5]. Functional copper transporters appear to be trimeric with each subunit having three TM regions and an extracellular N-terminus. CTR1 is considered to be a higher affinity copper transporter compared to CTR2. The stoichiometry of copper accumulation is unclear, but appears to be energy-independent [4]
SLC47 family of multidrug and toxin extrusion transporters in GtoPdb v.2023.1
Get PDFHuman multidrug and toxin extrusion MATE1 and MATE2-K are H+/organic cation antiporters [1]. They are predominantly expressed in the kidney and play a role in renal tubular secretion of cationic drugs
Succinate receptor in GtoPdb v.2023.1
Get PDFNomenclature as recommended by NC-IUPHAR [8]. The succinate receptor (GPR91, SUCNR1) is activated by the tricarboxylic acid (or Krebs) cycle intermediate succinate and other dicarboxylic acids with less clear physiological relevance such as maleate [17]. Since its pairing with its endogenous ligand in 2004, intense research has focused on the receptor-ligand pair role in various (patho)physiological processes such as regulation of renin production [17, 39], ischemia injury [17], fibrosis [25], retinal angiogenesis [34], inflammation [25, 23], immune response [32], obesity [44, 26, 21], diabetes [42, 22, 39], platelet aggregation [38, 36] or cancer [28, 46]. The succinate receptor is coupled to Gi/o [11, 17] and Gq/11 protein families [31, 17, 40]. Although the receptor is, upon ligand addition, rapidly desensitized [19, 31], and in some cells internalized [17], it seems to recruit arrestins weakly [10]. The cellular activation of the succinate receptor triggers various signalling pathways such as decrease of cAMP levels, [Ca2+]i mobilization and activation of kinases (ERK, c-Jun, Akt, Src, p38, PI3Kβ, etc.) [12]. The receptor is broadly expressed but is notably abundant in immune cells (M2 macrophages [40, 21], monocytes [32], immature dendritic cells [32], adipocytes [44], platelets [38, 36], etc.) and in the kidney [17]
Integrins in GtoPdb v.2023.1
Get PDFIntegrins 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 \u27Catalytic receptors\u27 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
SLC23 family of ascorbic acid transporters in GtoPdb v.2023.3
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]
Coronavirus (CoV) proteins in GtoPdb v.2022.3
Get PDFCoronaviruses are large, often spherical, enveloped, single-stranded positive-sense RNA viruses, ranging in size from 80-220 nm. Their genomes and protein structures are highly conserved. Three coronaviruses have emerged over the last 20 years as serious human pathogens: SARS-CoV was identified as the causative agent in an outbreak in 2002-2003, Middle East respiratory syndrome (MERS) CoV emerged in 2012 and the novel coronavirus SARS-CoV-2 emerged in 2019-2020. SARS-CoV-2 is the virus responsible for the infectious disease termed COVID-19 (WHO Technical Guidance 2020)