IUPHAR/BPS Guide to Pharmacology CITE
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Cyclic nucleotide-regulated channels (CNG) in GtoPdb v.2025.4
Full text linkCyclic nucleotide-gated (CNG) channels are responsible for signalling in the primary sensory cells of the vertebrate visual and olfactory systems. CNG channels are voltage-independent cation channels formed as tetramers. Each subunit has 6TM, with the pore-forming domain between TM5 and TM6. CNG channels were first found in rod photoreceptors [83, 120], where light signals through rhodopsin and transducin to stimulate phosphodiesterase and reduce intracellular cyclic GMP level. This results in a closure of CNG channels and a reduced ‘dark current’. Similar channels were found in the cilia of olfactory neurons [181] and the pineal gland [71]. The cyclic nucleotides bind to a domain in the C terminus of the subunit protein: other channels directly binding cyclic nucleotides include hyperpolarisation-activated, cyclic nucleotide-gated channels (HCN), ether-a-go-go and certain plant potassium channels.The HCN channels are cation channels that are activated by hyperpolarisation at voltages negative to ~-50 mV. The cyclic nucleotides cyclic AMP and cyclic GMP directly bind to the cyclic nucleotide-binding domain of HCN channels and shift their activation curves to more positive voltages, thereby enhancing channel activity. HCN channels underlie pacemaker currents found in many excitable cells including cardiac cells and neurons [65, 192]. In native cells, these currents have a variety of names, such as Ih, Iq and If. The four known HCN channels have six transmembrane domains and form tetramers. It is believed that the channels can form heteromers with each other, as has been shown for HCN1 and HCN4 [2]. High resolution structural studies of CNG and HCN channels has provided insight into the gating processes of these channels [139, 146, 140]. A standardised nomenclature for CNG and HCN channels has been proposed by the NC-IUPHAR Subcommittee on voltage-gated ion channels [108]
Complement peptide receptors in GtoPdb v.2025.3
Full text linkComplement peptide receptors (nomenclature as agreed by the NC-IUPHAR subcommittee on Complement peptide receptors [116]) are activated by the endogenous ~75 amino-acid anaphylatoxin polypeptides C3a and C5a, generated upon stimulation of the complement cascade. C3a and C5a exert their functions through binding to their receptors (C3a receptor, C5a receptor 1 and C5a receptor 2), causing cell recruitment and triggering cellular degranulation that contributes to local inflammation
Angiotensin receptors in GtoPdb v.2025.3
Full text linkThe actions of angiotensin II (Ang II) are mediated by AT1 and AT2 receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Angiotensin receptors [63, 155]), which have around 30% sequence similarity. The octapeptide angiotensin II and the heptapeptide angiotensin III are endogenous ligands. The "sartan" family drugs such as losartan, candesartan, olmesartan, telmisartan, etc. are clinically used AT1 receptor blockers
Adhesion Class GPCRs in GtoPdb v.2025.3
Full text linkAdhesion GPCRs are structurally identified on the basis of a large extracellular region, similar to the Class B GPCR, but which is linked to the 7TM region by a GPCR autoproteolysis-inducing (GAIN) domain [15] containing a GPCR proteolysis site (GPS). The N-terminal extracellular region often shares structural homology with adhesive domains (e.g. cadherins, immunolobulin, lectins) facilitating inter- and matricellular interactions and leading to the term adhesion GPCR [120, 468]. Several receptors have been suggested to function as mechanosensors [355, 322, 442, 49, 327]. Cryo-EM structures of the 7-transmembrane domain of several adhesion GPCRs have been determined recently [326, 31, 450, 241, 334, 336, 490, 327]. The nomenclature of these receptors was revised in 2015 as recommended by NC-IUPHAR and the Adhesion GPCR Consortium [145]
3C. 3-Ketosteroid receptors in GtoPdb v.2025.3
Full text linkSteroid hormone receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [75, 221, 3]) are nuclear hormone receptors of the NR3 class, with endogenous agonists that may be divided into 3-hydroxysteroids (estrone and 17β-estradiol) and 3-ketosteroids (dihydrotestosterone [DHT], aldosterone, cortisol, corticosterone, progesterone and testosterone). For rodent GR and MR, the physiological ligand is corticosterone rather than cortisol. Clinically-used drugs interacting with the 3-ketosteroid receptors include testosterone (AR), methylprednisolone (GR), eplerenone (MR), and medroxyprogesterone (PR)
Calcium activated chloride channel (CaCC) in GtoPdb v.2025.3
Full text linkChloride channels activated by intracellular Ca2+ (CaCC) are widely expressed in excitable and non-excitable cells where they perform diverse functions [25]. CaCCs are activated by a rise in intracellular free Ca2+ concentration ([Ca2+]i), typically following activation of Gq protein coupled receptors (GqPCR). This section centres on CaCC channels encoded by the TMEM16A gene (HUGO gene nomenclature: Anoctamin 1). The TMEM16 family consists of 10 paralogs (TMEM16A-K; Anoctamin 1-10). The TMEM16A and TMEM16B genes (ANO1 and ANO2) encode for CaCCs, while the other members function as lipid scramblases or have combined scramblase and non-selective ion channel function [26, 46, 18, 1, 41]. TMEM16A has a broad tissue distribution and a variety of established cellular roles, while the main physiological role for TMEM16B identified thus far is in olfaction [31, 16]. Alternative splicing regulates the voltage- and Ca2+-dependence of TMEM16A and such post-transcriptional process may be tissue-specific and contribute to functional diversity [19]. TMEM16A is a potential drug target for a variety of conditions spanning from respiratory to vascular (see "Comments" section for further detail)
SLCO family of organic anion transporting polypeptides in GtoPdb v.2025.3
Full text linkThe SLCO superfamily is comprised of the organic anion transporting polypeptides (OATPs). The 11 human OATPs are divided into 6 families and ten subfamilies based on amino acid identity. These proteins are located on the plasma membrane of cells throughout the body. They have 12 TM domains and intracellular termini, with multiple putative glycosylation sites. OATPs mediate the sodium-independent uptake of a wide range of amphiphilic substrates, including many drugs and toxins. Due to the multispecificity of these proteins, this guide lists classes of substrates and inhibitors for each family member. More comprehensive lists of substrates, inhibitors, and their relative affinities may be found in the review articles listed below
Type IV RTKs: VEGF (vascular endothelial growth factor) receptor family in GtoPdb v.2025.3
Full text linkVEGF receptors are homo- and heterodimeric proteins, which are characterized by seven Ig-like loops in their extracellular domains and a split kinase domain in the cytoplasmic region. They are key regulators of angiogenesis and lymphangiogenesis; as such, they have been the focus of drug discovery for conditions such as metastatic cancer. Splice variants of VEGFR1 and VEGFR2 generate truncated proteins limited to the extracellular domains, capable of homodimerisation and binding VEGF ligands as a soluble, non-signalling entity. Ligands at VEGF receptors are typically homodimeric. VEGFA is able to activate VEGFR1 and VEGFR2 homodimers, VEGFR1/2 heterodimers and VEGFR2/3 heterodimers. VEGFB and placental growth factor activate VEGFR1 homodimers, while VEGFC and VEGFD activate VEGFR2/3 heterodimers and VEGFR3 homodimers, and, following proteolysis, VEGFR2 homodimers
SLC54 Mitochondrial pyruvate carriers in GtoPdb v.2025.3
Full text linkThe mitochondrial pyruvate carrier (MPC) is composed of SLC54 family members (MPC1 or MPC1L and MPC2) [1, 5, 10], which form functional hetero-dimers [9, 8]. The MPC is expressed in the inner mitochondrial membrane and is responsible for the import of pyruvate into mitochondria [1, 5]. Pyruvate is oxidized to acetyl-CoA by pyruvate dehydrogenase which is localized in the mitochondrial matrix. Ubiquitous disruption of either MPC1 or MPC2 expression results in embryonic lethality [11, 12]. Clinically relevant concentrations of the insulin sensitizers, thiazolidinediones, inhibit the MPC [3]. Other clinically relevant inhibitors of the MPC complex are lonidamine [7, 8], quinolone antibacterials [6], entacapone and nitrofurantoin [8]
Coronavirus (CoV) proteins in GtoPdb v.2025.3
Full text linkCoronaviruses 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)