IUPHAR/BPS Guide to Pharmacology CITE
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Neuropeptide Y receptors in GtoPdb v.2025.3
Full text linkNeuropeptide Y (NPY) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Neuropeptide Y Receptors [159]) 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, [140]). 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 [85]. Three-dimensional structures have been determined for subtype active receptors Y1, Y2 and Y4 [216, 115] and inactive antagonist bound Y1 and Y2 receptors [245, 215]. 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 [63]. 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)
Parathyroid hormone receptors in GtoPdb v.2025.3
Full text linkThe parathyroid hormone receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Parathyroid Hormone Receptors [50]) are class B G protein-coupled receptors. The parathyroid hormone (PTH)/parathyroid hormone-related protein (PTHrP) receptor (PTH1 receptor) is activated by : PTH (84 amino acids), and PTHrP (141 amino-acids) and related N-terminal peptides (PTH-(1-34), PTHrP-(1-36)). The parathyroid hormone 2 receptor (PTH2 receptor) is activated by the precursor-derived peptide TIP39 (39 amino acids) and PTH. [125I]PTH may be used to label both PTH1 and PTH2 receptors. The structure of a long-active PTH analogue (LA-PTH, an hybrid of PTH-(1-13) and PTHrP-(14-36)) bound to the PTH1 receptor-Gs complex has been resolved by cryo-electron microscopy [150]. Another structure of a PTH-(1-34) analog bound to a thermostabilized inactive PTH1 receptor has been obtained with X-ray crytallography [35]
Ionotropic glutamate receptors in GtoPdb v.2025.3
Full text linkThe 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 [60, 99, 163]. 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) [106, 74, 115, 163, 88]. The X-ray structure of a homomeric ionotropic glutamate receptor (GluA2- see below) has recently been solved at 3.6Å resolution [151] and although providing the most complete structural information current available may not representative of the subunit arrangement of, for example, the heteromeric NMDA receptors [77]. 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 [60, 72, 34, 83, 44, 122, 27, 71, 163, 120, 121, 171]. 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 [31]. 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 [43, 28]. 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 [50, 106, 77]. 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 [45, 110, 161, 70]). 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; [94, 127, 126]). 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 [127, 71, 126]). Kainate receptors may also exhibit \u27metabotropic\u27 functions [94, 139]. As found for AMPA receptors, kainate receptors are modulated by auxiliary subunits (Neto proteins, [126, 95]). An important function difference between AMPA and kainate receptors is that the latter require extracellular Na+ and Cl- for their activation [13, 128]. 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 [147, 69]. 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 [94, 126]. Native AMPA and kainate receptors displaying differential channel conductances, Ca2+ permeabilites and sensitivity to block by intracellular polyamines have been identified [33, 69, 98]. 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 [110]. Splice variants of GluK1-3 also exist which affects their trafficking [94, 126]
P2X receptors in GtoPdb v.2025.3
Full text linkP2X receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on P2X Receptors [49, 150]) have a trimeric topology [121, 132, 148, 201] with two putative TM domains per P2X subunit, gating primarily Na+, K+ and Ca2+, exceptionally Cl-. The Nomenclature Subcommittee has recommended that for P2X receptors, structural criteria should be the initial basis for nomenclature where possible. X-ray crystallography indicates that functional P2X receptors are trimeric and three agonist molecules are required to bind to a single trimeric assembly in order to activate it [121, 148, 97, 105, 181]. Native receptors may occur as either homotrimers (e.g. P2X1 in smooth muscle) or heterotrimers (e.g. P2X2:P2X3 in the nodose ganglion [284], P2X1:P2X5 in mouse cortical astrocytes [166], and P2X2:P2X5 in mouse dorsal root ganglion, spinal cord and mid pons [53, 238]. P2X2, P2X4 and P2X7 receptor activation can lead to influx of large cationic molecules, such as NMDG+, Yo-Pro, ethidium or propidium iodide [215]. The permeability of the P2X7 receptor is modulated by the amount of cholesterol in the plasma membrane [197]. The hemi-channel pannexin-1 was initially implicated in the action of P2X7 [216], but not P2X2, receptors [41], but this interpretation is probably misleading [219]. Convincing evidence now supports the view that the activated P2X7 receptor is immediately permeable to large cationic molecules, but influx proceeds at a much slower pace than that of the small cations Na+, K+, and Ca2+ [67]
Two-pore domain potassium channels (K2P) in GtoPdb v.2025.3
Full text linkThe 4TM family of K channels mediate many of the background potassium currents observed in native cells. They are open across the physiological voltage-range and are regulated by a wide array of neurotransmitters and biochemical mediators. The pore-forming α-subunit contains two pore loop (P) domains and two subunits assemble to form one ion conduction pathway lined by four P domains. It is important to note that single channels do not have two pores but that each subunit has two P domains in its primary sequence; hence the name two-pore domain, or K2P channels (and not two-pore channels). Some of the K2P subunits can form heterodimers across subfamilies (e.g. K2P3.1 with K2P9.1). The nomenclature of 4TM K channels in the literature is still a mixture of IUPHAR and common names. The suggested division into subfamilies, described in the More detailed introduction, is based on similarities in both structural and functional properties within subfamilies and this explains the "common abbreviation" nomenclature in the tables below
1A. Thyroid hormone receptors in GtoPdb v.2025.3
Full text linkThyroid hormone receptors (TRs, nomenclature as agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [13, 2]) are nuclear hormone receptors of the NR1A family, with diverse roles regulating macronutrient metabolism, cognition and cardiovascular homeostasis. TRs are activated by thyroxine (T4) and thyroid hormone (triiodothyronine). Once activated by a ligand, the receptor acts as a transcription factor either as a monomer, homodimer or heterodimer with members of the retinoid X receptor family. NH-3 has been described as an antagonist at TRs with modest selectivity for TRβ [43]
2A. Hepatocyte nuclear factor-4 receptors in GtoPdb v.2025.3
Full text linkThe nomenclature of hepatocyte nuclear factor-4 receptors is agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [9, 3]. While linoleic acid has been identified as the endogenous ligand for HNF4α its function remains ambiguous [80]. HNF4γ has yet to be paired with an endogenous ligand
IL-12 receptor family in GtoPdb v.2025.3
Full text linkIL-12 receptors are a subfamily of the IL-6 receptor family. IL12RB1 is shared between receptors for IL-12 and IL-23; the functional agonist at IL-12 receptors is a heterodimer of IL-12A/IL-12B, while that for IL-23 receptors is a heterodimer of IL-12B/IL-23A
Type I RTKs: ErbB (epidermal growth factor) receptor family in GtoPdb v.2025.3
Full text linkErbB family receptors are Class I receptor tyrosine kinases [51]. EGFR (HER1) was the first member of the family to be identified. ERBB2 (also known as HER-2 or NEU) appears to act as an essential partner for the other members of the family without itself being activated by a cognate ligand [52]. Ligands of the ErbB family of receptors are peptides, many of which are generated by proteolytic cleavage of cell-surface proteins. HER/ErbB is the viral counterpart to the receptor tyrosine kinase EGFR. All family members heterodimerize with each other to activate downstream signalling pathways and are aberrantly expressed in many cancers, particularly forms of breast cancer and lung cancer. Mutations in the EGFR are responsible for acquired resistance to tyrosine kinase inhibitor chemotherapeutics
Integrins in GtoPdb v.2025.3
Full text linkIntegrins 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) tirofiban (αIIbβ3) for short term prevention of coronary thrombosis (abciximab, the first clinically approved (1994) chimeric monoclonal antibody, is no longer available for clinical use), (2) vedolizumab (α4β7) to reduce gastrointestinal inflammation, and (3) natalizumab (α4β1) in some cases of severe multiple sclerosis. Drugs targeting multiple integrins are under investigation for the treatment of dry eye disease, e.g., risuteganib, an anti-integrin peptide [44]