IUPHAR/BPS Guide to Pharmacology CITE
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Prostanoid receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database
Get PDFProstanoid receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Prostanoid Receptors [644]) are activated by the endogenous ligands prostaglandins PGD2, PGE1, PGE2 , PGF2α, PGH2, prostacyclin [PGI2] and thromboxane A2. Measurement of the potency of PGI2 and thromboxane A2 is hampered by their instability in physiological salt solution; they are often replaced by cicaprost and U46619, respectively, in receptor characterization studies
Vasopressin and oxytocin receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database
Get PDFVasopressin (AVP) and oxytocin (OT) receptors (nomenclature as recommended by NC-IUPHAR [92]) are activated by the endogenous cyclic nonapeptides vasopressin and oxytocin. These peptides are derived from precursors which also produce neurophysins (neurophysin I for oxytocin; neurophysin II for vasopressin). Vasopressin and oxytocin differ at only 2 amino acids (positions 3 and 8). There are metabolites of these neuropeptides that may be biologically active [67]
Nicotinic acetylcholine receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database
Get PDFNicotinic acetylcholine receptors are members of the Cys-loop family of transmitter-gated ion channels that includes the GABAA, strychnine-sensitive glycine and 5-HT3 receptors [210, 3, 155, 220, 252]. All nicotinic receptors are pentamers in which each of the five subunits contains four α-helical transmembrane domains. Genes encoding a total of 17 subunits (α1-10, β1-4, γ, δ and ε) have been identified [117]. All subunits with the exception of α8 (present in avian species) have been identified in mammals. All α subunits possess two tandem cysteine residues near to the site involved in acetylcholine binding, and subunits not named α lack these residues [155]. The orthosteric ligand binding site is formed by residues within at least three peptide domains on the α subunit (principal component), and three on the adjacent subunit (complementary component). nAChRs contain several allosteric modulatory sites. One such site, for positive allosteric modulators (PAMs) and allosteric agonists, has been proposed to reside within an intrasubunit cavity between the four transmembrane domains [257, 85]; see also [103]). The high resolution crystal structure of the molluscan acetylcholine binding protein, a structural homologue of the extracellular binding domain of a nicotinic receptor pentamer, in complex with several nicotinic receptor ligands (e.g.[33]) and the crystal structure of the extracellular domain of the α1 subunit bound to α-bungarotoxin at 1.94 Å resolution [53], has revealed the orthosteric binding site in detail (reviewed in [210, 117, 37, 193]). Nicotinic receptors at the somatic neuromuscular junction of adult animals have the stoichiometry (α1)2β1δε, whereas an extrajunctional (α1)2β1γδ receptor predominates in embryonic and denervated skeletal muscle and other pathological states. Other nicotinic receptors are assembled as combinations of α(2-6) and &beta(2-4) subunits. For α2, α3, α4 and β2 and β4 subunits, pairwise combinations of α and β (e.g. α3β4 and α4β2) are sufficient to form a functional receptor in vitro, but far more complex isoforms may exist in vivo (reviewed in [94, 91, 155]). There is strong evidence that the pairwise assembly of some α and β subunits can occur with variable stoichiometry [e.g. (α4)2(β2)2 or (α4)3(β2)2] which influences the biophysical and pharmacological properties of the receptor [155]. α5 and β3 subunits lack function when expressed alone, or pairwise, but participate in the formation of functional hetero-oligomeric receptors when expressed as a third subunit with another α and β pair [e.g. α4α5αβ2, α4αβ2β3, α5α6β2, see [155] for further examples]. The α6 subunit can form a functional receptor when co-expressed with β4 in vitro, but more efficient expression ensues from incorporation of a third partner, such as β3 [256]. The α7, α8, and α9 subunits form functional homo-oligomers, but can also combine with a second subunit to constitute a hetero-oligomeric assembly (e.g. α7β2 and α9α10). For functional expression of the α10 subunit, co-assembly with α9 is necessary. The latter, along with the α10 subunit, appears to be largely confined to cochlear and vestibular hair cells. Comprehensive listings of nicotinic receptor subunit combinations identified from recombinant expression systems, or in vivo, are given in [155]. In addition, numerous proteins interact with nicotinic ACh receptors modifying their assembly, trafficking to and from the cell surface, and activation by ACh (reviewed by [154, 9, 115]).The nicotinic receptor Subcommittee of NC-IUPHAR has recommended a nomenclature and classification scheme for nicotinic acetylcholine (nACh) receptors based on the subunit composition of known, naturally- and/or heterologously-expressed nACh receptor subtypes [139]. Headings for this table reflect abbreviations designating nACh receptor subtypes based on the predominant α subunit contained in that receptor subtype. An asterisk following the indicated α subunit denotes that other subunits are known to, or may, assemble with the indicated α subunit to form the designated nACh receptor subtype(s). Where subunit stoichiometries within a specific nACh receptor subtype are known, numbers of a particular subunit larger than 1 are indicated by a subscript following the subunit (enclosed in parentheses – see also [44])
Transient Receptor Potential channels (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database
Get PDFThe TRP superfamily of channels (nomenclature as agreed by NC-IUPHAR [145, 915]), whose founder member is the Drosophila Trp channel, exists in mammals as six families; TRPC, TRPM, TRPV, TRPA, TRPP and TRPML based on amino acid homologies. TRP subunits contain six putative transmembrane domains and assemble as homo- or hetero-tetramers to form cation selective channels with diverse modes of activation and varied permeation properties (reviewed by [630]). Established, or potential, physiological functions of the individual members of the TRP families are discussed in detail in the recommended reviews and in a number of books [344, 589, 979, 216]. The established, or potential, involvement of TRP channels in disease is reviewed in [384, 588] and [591], together with a special edition of Biochemica et Biophysica Acta on the subject [588]. Additional disease related reviews, for pain [542], stroke [967], sensation and inflammation [843], itch [109], and airway disease [261, 896], are available. The pharmacology of most TRP channels has been advanced in recent years. Broad spectrum agents are listed in the tables along with more selective, or recently recognised, ligands that are flagged by the inclusion of a primary reference. See Rubaiy (2019) for a review of pharmacological tools for TRPC1/C4/C5 channels [692]. Most TRP channels are regulated by phosphoinostides such as PtIns(4,5)P2 although the effects reported are often complex, occasionally contradictory, and likely to be dependent upon experimental conditions, such as intracellular ATP levels (reviewed by [862, 592, 689]). Such regulation is generally not included in the tables.When thermosensitivity is mentioned, it refers specifically to a high Q10 of gating, often in the range of 10-30, but does not necessarily imply that the channel\u27s function is to act as a \u27hot\u27 or \u27cold\u27 sensor. In general, the search for TRP activators has led to many claims for temperature sensing, mechanosensation, and lipid sensing. All proteins are of course sensitive to energies of binding, mechanical force, and temperature, but the issue is whether the proposed input is within a physiologically relevant range resulting in a response. TRPA (ankyrin) familyTRPA1 is the sole mammalian member of this group (reviewed by [246]). TRPA1 activation of sensory neurons contribute to nociception [356, 763, 516]. Pungent chemicals such as mustard oil (AITC), allicin, and cinnamaldehyde activate TRPA1 by modification of free thiol groups of cysteine side chains, especially those located in its amino terminus [491, 47, 311, 493]. Alkenals with α, β-unsaturated bonds, such as propenal (acrolein), butenal (crotylaldehyde), and 2-pentenal can react with free thiols via Michael addition and can activate TRPA1. However, potency appears to weaken as carbon chain length increases [21, 47]. Covalent modification leads to sustained activation of TRPA1. Chemicals including carvacrol, menthol, and local anesthetics reversibly activate TRPA1 by non-covalent binding [364, 438, 923, 922]. TRPA1 is not mechanosensitive under physiological conditions, but can be activated by cold temperatures [365, 175]. The electron cryo-EM structure of TRPA1 [639] indicates that it is a 6-TM homotetramer. Each subunit of the channel contains two short ‘pore helices’ pointing into the ion selectivity filter, which is big enough to allow permeation of partially hydrated Ca2+ ions. TRPC (canonical) familyMembers of the TRPC subfamily (reviewed by [239, 673, 14, 4, 79, 382, 638, 55]) fall into the subgroups outlined below. TRPC2 is a pseudogene in humans. It is generally accepted that all TRPC channels are activated downstream of Gq/11-coupled receptors, or receptor tyrosine kinases (reviewed by [661, 814, 915]). A comprehensive listing of G-protein coupled receptors that activate TRPC channels is given in [4]. Hetero-oligomeric complexes of TRPC channels and their association with proteins to form signalling complexes are detailed in [14] and [383]. TRPC channels have frequently been proposed to act as store-operated channels (SOCs) (or compenents of mulimeric complexes that form SOCs), activated by depletion of intracellular calcium stores (reviewed by [640, 14, 665, 703, 954, 132, 626, 51, 133]). However, the weight of the evidence is that they are not directly gated by conventional store-operated mechanisms, as established for Stim-gated Orai channels. TRPC channels are not mechanically gated in physiologically relevant ranges of force. All members of the TRPC family are blocked by 2-APB and SKF96365 [295, 294]. Activation of TRPC channels by lipids is discussed by [55]. Important progress has been recently made in TRPC pharmacology [692, 529, 372, 87]. TRPC channels regulate a variety of physiological functions and are implicated in many human diseases [248, 56, 759, 879]. TRPC1/C4/C5 subgroup TRPC1 alone may not form a functional ion channel [191]. TRPC4/C5 may be distinguished from other TRP channels by their potentiation by micromolar concentrations of La3+. TRPC2 is a pseudogene in humans, but in other mammals appears to be an ion channel localized to microvilli of the vomeronasal organ. It is required for normal sexual behavior in response to pheromones in mice. It may also function in the main olfactory epithelia in mice [951, 625, 624, 952, 462, 988, 947].TRPC3/C6/C7 subgroup All members are activated by diacylglycerol independent of protein kinase C stimulation [295].TRPM (melastatin) familyMembers of the TRPM subfamily (reviewed by [230, 294, 640, 978]) fall into the five subgroups outlined below. TRPM1/M3 subgroupIn darkness, glutamate released by the photoreceptors and ON-bipolar cells binds to the metabotropic glutamate receptor 6 , leading to activation of Go . This results in the closure of TRPM1. When the photoreceptors are stimulated by light, glutamate release is reduced, and TRPM1 channels are more active, resulting in cell membrane depolarization. Human TRPM1 mutations are associated with congenital stationary night blindness (CSNB), whose patients lack rod function. TRPM1 is also found melanocytes. Isoforms of TRPM1 may present in melanocytes, melanoma, brain, and retina. In melanoma cells, TRPM1 is prevalent in highly dynamic intracellular vesicular structures [341, 609]. TRPM3 (reviewed by [615]) exists as multiple splice variants which differ significantly in their biophysical properties. TRPM3 is expressed in somatosensory neurons and may be important in development of heat hyperalgesia during inflammation (see review [803]). TRPM3 is frequently coexpressed with TRPA1 and TRPV1 in these neurons. TRPM3 is expressed in pancreatic beta cells as well as brain, pituitary gland, eye, kidney, and adipose tissue [614, 802]. TRPM3 may contribute to the detection of noxious heat [870].TRPM2TRPM2 is activated under conditions of oxidative stress (respiratory burst of phagocytic cells) and ischemic conditions. However, the direct activators are ADPR(P) and calcium. As for many ion channels, PIP2 must also be present (reviewed by [935]). Numerous splice variants of TRPM2 exist which differ in their activation mechanisms [200]. The C-terminal domain contains a TRP motif, a coiled-coil region, and an enzymatic NUDT9 homologous domain. TRPM2 appears not to be activated by NAD, NAAD, or NAADP, but is directly activated by ADPRP (adenosine-5\u27-O-disphosphoribose phosphate) [827]. TRPM2 is involved in warmth sensation [724], and contributes to neurological diseases [61]. Recent study shows that 2\u27-deoxy-ADPR is an endogenous TRPM2 superagonist [231]. TRPM4/5 subgroupTRPM4 and TRPM5 have the distinction within all TRP channels of being impermeable to Ca2+ [915]. A splice variant of TRPM4 (i.e.TRPM4b) and TRPM5 are molecular candidates for endogenous calcium-activated cation (CAN) channels [278]. TRPM4 is active in the late phase of repolarization of the cardiac ventricular action potential. TRPM4 deletion or knockout enhances beta adrenergic-mediated inotropy [507]. Mutations are associated with conduction defects [347, 507, 753]. TRPM4 has been shown to be an important regulator of Ca2+ entry in to mast cells [847] and dendritic cell migration [39]. TRPM5 in taste receptor cells of the tongue appears essential for the transduction of sweet, amino acid and bitter stimuli [460] TRPM5 contributes to the slow afterdepolarization of layer 5 neurons in mouse prefrontal cortex [439]. Both TRPM4 and TRPM5 are required transduction of taste stimuli [206].TRPM6/7 subgroupTRPM6 and 7 combine channel and enzymatic activities (‘chanzymes’). These channels have the unusual property of permeation by divalent (Ca2+, Mg2+, Zn2+) and monovalent cations, high single channel conductances, but overall extremely small inward conductance when expressed to the plasma membrane. They are inhibited by internal Mg2+ at ~0.6 mM, around the free level of Mg2+ in cells. Whether they contribute to Mg2+ homeostasis is a contentious issue. When either gene is deleted in mice, the result is embryonic lethality. The C-terminal kinase region is cleaved under unknown stimuli, and the kinase phosphorylates nuclear histones. TRPM7 is responsible for oxidant- induced Zn2+ release from intracellular vesicles [3] and contributes to intestinal mineral absorption essential for postnatal survival [532]. TRPM8Is a channel activated by cooling and pharmacological agents evoking a ‘cool’ sensation and participates in the thermosensation of cold temperatures [50, 147, 186] reviewed by [864, 481, 391, 556]. TRPML (mucolipin) familyThe TRPML family [676, 964, 670, 926, 156] consists of three mammalian members (TRPML1-3). TRPML channels are probably restricted to intracellular vesicles and mutations in the gene (MCOLN1) encoding TRPML1 (mucolipin-1) cause the neurodegenerative disorder mucolipidosis type IV (MLIV) in man. TRPML1 is a cation selective ion channel that is important for sorting/transport of endosomes in the late endocytotic pathway and specifically, fission from late endosome-lysosome hybrid vesicles and lysosomal exocytosis [704]. TRPML2 and TRPML3 show increased channel activity in low extracellular sodium and are activated by similar small molecules [270]. A naturally occurring gain of function mutation in TRPML3 (i.e. A419P) results in the varitint waddler (Va) mouse phenotype (reviewed by [676, 593]). TRPP (polycystin) familyThe TRPP family (reviewed by [179, 177, 252, 905, 320]) or PKD2 family is comprised of PKD2 (PC2), PKD2L1 (PC2L1), PKD2L2 (PC2L2), which have been renamed TRPP1, TRPP2 and TRPP3, respectively [915]. It should also be noted that the nomenclature of PC2 was TRPP2 in old literature. However, PC2 has been uniformed to be called TRPP2 [293]. PKD2 family channels are clearly distinct from the PKD1 family, whose function is unknown. PKD1 and PKD2 form a hetero-oligomeric complex with a 1:3 ratio. [775]. Although still being sorted out, TRPP family members appear to be 6TM spanning nonselective cation channels. TRPV (vanilloid) familyMembers of the TRPV family (reviewed by [849]) can broadly be divided into the non-selective cation channels, TRPV1-4 and the more calcium selective channels TRPV5 and TRPV6.TRPV1-V4 subfamilyTRPV1 is involved in the development of thermal hyperalgesia following inflammation and may contribute to the detection of noxius heat (reviewed by [660, 756, 786]). Numerous splice variants of TRPV1 have been described, some of which modulate the activity of TRPV1, or act in a dominant negative manner when co-expressed with TRPV1 [722]. The pharmacology of TRPV1 channels is discussed in detail in [280] and [868]. TRPV2 is probably not a thermosensor in man [635], but has recently been implicated in innate immunity [469]. TRPV3 and TRPV4 are both thermosensitive. There are claims that TRPV4 is also mechanosensitive, but this has not been established to be within a physiological range in a native environment [106, 454].TRPV5/V6 subfamily TRPV5 and TRPV6 are highly expressed in placenta, bone, and kidney. Under physiological conditions, TRPV5 and TRPV6 are calcium selective channels involved in the absorption and reabsorption of calcium across intestinal and kidney tubule epithelia (reviewed by [901, 168, 558, 227])
SLC28 and SLC29 families of nucleoside transporters (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database
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
ABCG subfamily (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database
Get PDFThis family of \u27half-transporters\u27 act as homo- or heterodimers; particularly ABCG5 and ABCG8 are thought to be obligate heterodimers. The ABCG5/ABCG heterodimer sterol transporter structure has been determined [4], suggesting an extensive intracellular nucleotide binding domain linked to the transmembrane domains by a fold in the primary sequence. The functional ABCG2 transporter appears to be a homodimer with structural similarities to the ABCG5/ABCG8 heterodimer [7]
Pattern recognition receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database
Get PDFPattern Recognition Receptors (PRRs, [89]) (nomenclature as agreed by NC-IUPHAR sub-committee on Pattern Recognition Receptors, [17]) participate in the innate immune response to microbial agents, the stimulation of which leads to activation of intracellular enzymes and regulation of gene transcription. PRRs express multiple leucine-rich regions to bind a range of microbially-derived ligands, termed PAMPs or pathogen-associated molecular patterns or endogenous ligands, termed DAMPS or damage-associated molecular patterns. These include peptides, carbohydrates, peptidoglycans, lipoproteins, lipopolysaccharides, and nucleic acids. PRRs include both cell-surface and intracellular proteins. PRRs may be divided into signalling-associated members, identified here, and endocytic members, the function of which appears to be to recognise particular microbial motifs for subsequent cell attachment, internalisation and destruction. Some are involved in inflammasome formation, and modulation of IL-1β cleavage and secretion, and others in the initiation of the type I interferon response. PRRs included in the Guide To PHARMACOLOGY are:Catalytic PRRs (see links below this overview)Toll-like receptors (TLRs)Nucleotide-binding oligomerization domain, leucine-rich repeat containing receptors (NLRs, also known as NOD (Nucleotide oligomerisation domain)-like receptors)RIG-I-like receptors (RLRs)Caspase 4 and caspase 5 Non-catalytic PRRsAbsent in melanoma (AIM)-like receptors (ALRs)C-type lectin-like receptors (CLRs)Other pattern recognition receptorsAdvanced glycosylation end-product specific receptor (RAGE
Bile acid receptor (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database
Get PDFThe bile acid receptor (GPBA) responds to bile acids produced during the liver metabolism of cholesterol. Selective agonists are promising drugs for the treatment of metabolic disorders, such as type II diabetes, obesity and atherosclerosis
Bradykinin receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database
Get PDFBradykinin (or kinin) receptors (nomenclature as agreed by the NC-IUPHAR subcommittee on Bradykinin (kinin) Receptors [76]) are activated by the endogenous peptides bradykinin (BK), [des-Arg9]bradykinin, Lys-BK (kallidin), [des-Arg10]kallidin, [Phospho-Ser6]-Bradykinin, T-kinin (Ile-Ser-BK), [Hyp3]bradykinin and Lys-[Hyp3]-bradykinin. Variation in pharmacology and activity of B1 and B2 receptor antagonists at species orthologs has been documented. icatibant (Hoe140, Firazir) is approved in North America and Europe for the treatment of acute attacks of hereditary angioedema
Calcium-sensing receptor (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database
Get PDFThe calcium-sensing receptor (CaS, provisional nomenclature as recommended by NC-IUPHAR [44]) responds to multiple endogenous ligands, including extracellular calcium and other divalent/trivalent cations, polyamines and polycationic peptides, L-amino acids (particularly L-Trp and L-Phe), glutathione and various peptide analogues, ionic strength and extracellular pH (reviewed in [74]). While divalent/trivalent cations, polyamines and polycations are CaS receptor agonists [14, 106], L-amino acids, glutamyl peptides, ionic strength and pH are allosteric modulators of agonist function [34, 44, 58, 104, 105]. Indeed, L-amino acids have been identified as "co-agonists", with both concomitant calcium and L-amino acid binding required for full receptor activation [143, 51]. The sensitivity of the CaS receptor to primary agonists is increased by elevated extracellular pH [17] or decreased extracellular ionic strength [105]. This receptor bears no sequence or structural relation to the plant calcium receptor, also called CaS