Transient Receptor Potential channels (TRP) in GtoPdb v.2025.1 Article Swipe

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Nathaniel T. Blair , David D. McKemy , Bernd Nilius , Elena Oancea , Grzegorz Owsianik , Antonio Riccio , Rajan Sah , Stephanie C. Stotz , Jinbin Tian , Dan Tong , Joris Vriens , Long‐Jun Wu , Haoxing Xu , Fan Yang , Wei Yang , Lixia Yue , Qiang Liu , Boyi Liu , Ana I. Caceres , Ingrid Carvacho , Dipayan Chaudhuri , David E. Clapham , Katrien De Clercq , Markus Delling , Julia F. Doerner , Lu Fan , Christian Grimm , Kotdaji Ha , Meiqin Hu , Sairam V. Jabba , Sven‐Eric Jordt , David Julius , Kristopher T. Kahle , Michael X. Zhu · YOU? · · 2025 · Open Access · · DOI: https://doi.org/10.2218/gtopdb/f78/2025.1

The TRP superfamily of channels (nomenclature as agreed by NC-IUPHAR [177, 1080]), 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 TM domains and assemble as homo- or hetero-tetramers to form cation selective channels with diverse modes of activation and varied permeation properties (reviewed by [734]). 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 [404, 690, 1163, 258]. The established, or potential, involvement of TRP channels in disease [1134] is reviewed in [452, 689], [692] and [468], together with a special edition of Biochemica et Biophysica Acta on the subject [689]. Additional disease related reviews, for pain [637], stroke [1143], sensation and inflammation [994], itch [130], and airway disease [313, 1058], 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 [810]. 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 [1015, 693, 806]). 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's function is to act as a 'hot' or 'cold' 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 [295]). TRPA1 activation of sensory neurons contribute to nociception [417, 895, 606]. 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 [579, 60, 368, 581]. 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 [26, 60]. Covalent modification leads to sustained activation of TRPA1. Chemicals including carvacrol, menthol, and local anesthetics reversibly activate TRPA1 by non-covalent binding [428, 515, 1089, 1088]. TRPA1 is not mechanosensitive under physiological conditions, but can be activated by cold temperatures [429, 213]. The electron cryo-EM structure of TRPA1 [745] 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 [286, 783, 18, 4, 94, 450, 744, 70]) 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 [770, 959, 1080]). 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 [18] and [451]. 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 [746, 18, 775, 825, 1129, 157, 730, 64, 158]). 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 [350, 349]. Activation of TRPC channels by lipids is discussed by [70]. Important progress has been recently made in TRPC pharmacology [810, 623, 440, 102, 856, 192, 293]. TRPC channels regulate a variety of physiological functions and are implicated in many human diseases [298, 71, 890, 1038, 1032, 154, 103, 565, 918, 412]. TRPC1/C4/C5 subgroup TRPC1 alone may not form a functional ion channel [230]. The structures of the apo and antagonist-bound states of TRPC1/TRPC4 heteromeric channels have been resolved by cryo-EM [1070]. 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 [1122, 727, 728, 1123, 543, 1176, 1117].TRPC3/C6/C7 subgroup All members are activated by diacylglycerol independent of protein kinase C stimulation [350].TRPM (melastatin) familyMembers of the TRPM subfamily (reviewed by [277, 349, 746, 1159]) 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 [401, 712]. TRPM3 (reviewed by [718]) 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 [947]). 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 [717, 946]. TRPM3 may contribute to the detection of noxious heat [1024]. TRPM2TRPM2 is activated under conditions of oxidative stress (respiratory burst of phagocytic cells). The direct activators are calcium, adenosine diphosphate ribose (ADPR) [976] and cyclic ADPR (cADPR) [1126]. As for many ion channels, PI(4,5)P2 must also be present [1117]. Numerous splice variants of TRPM2 exist which differ in their activation mechanisms [240]. Recent studies have reported structures of human (hs) TRPM2, which demonstrate two ADPR binding sites in hsTRPM2, one in the N-terminal MHR1/2 domain and the other in the C-terminal NUDT9-H domain. In addition, one Ca2+ binding site in the intracellular S2-S3 loop is revealed and proposed to mediate Ca2+ binding that induces conformational changes leading the ADPR-bound closed channel to open [390, 1034]. Meanwhile, a quadruple-residue motif (979FGQI982) was identified as the ion selectivity filter and a gate to control ion permeation in hsTRPM2 [1128]. TRPM2 is involved in warmth sensation [853], and contributes to several diseases [76]. TRPM2 interacts with extra synaptic NMDA receptors (NMDAR) and enhances NMDAR activity in ischemic stroke [1172]. Activation of TRPM2 in macrophages promotes atherosclerosis [1173, 1155]. Moreover, silica nanoparticles induce lung inflammation in mice via ROS/PARP/TRPM2 signaling-mediated lysosome impairment and autophagy dysfunction [1035]. Recent studies have designed various compounds for their potential to selectively inhibit the TRPM2 channel, including ACA derivatives A23, and 2,3-dihydroquinazolin-4(1H)-one derivatives [1145, 1147]. TRPM4/5 subgroupTRPM4 and TRPM5 have the distinction within all TRP channels of being impermeable to Ca2+ [1080]. A splice variant of TRPM4 (i.e.TRPM4b) and TRPM5 are molecular candidates for endogenous calcium-activated cation (CAN) channels [330]. TRPM4 is active in the late phase of repolarization of the cardiac ventricular action potential. TRPM4 deletion or knockout enhances beta adrenergic-mediated inotropy [597]. Mutations are associated with conduction defects [407, 597, 884]. TRPM4 has been shown to be an important regulator of Ca2+ entry in to mast cells [999] and dendritic cell migration [52]. TRPM5 in taste receptor cells of the tongue appears essential for the transduction of sweet, amino acid and bitter stimuli [541] TRPM5 contributes to the slow afterdepolarization of layer 5 neurons in mouse prefrontal cortex [517]. Both TRPM4 and TRPM5 are required transduction of taste stimuli [247]. TRPM6/7 subgroupTRPM6 and 7 combine channel and enzymatic activities (‘chanzymes’) [173]. 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 is

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Transient Receptor Potential channels (TRP) in GtoPdb v.2025.1

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Nathaniel T. Blair, David D. McKemy, Bernd Nilius, Elena Oancea, Grzegorz Owsianik, Antonio Riccio, Rajan Sah, Stephanie C. Stotz, Jinbin Tian, Dan Tong, Joris Vriens, Long‐Jun Wu, Haoxing Xu, Fan Yang, Wei Yang, Lixia Yue, Qiang Liu, Boyi Liu, Ana I. Caceres, Ingrid Carvacho, Dipayan Chaudhuri, David E. Clapham, Katrien De Clercq, Markus Delling, Julia F. Doerner, Lu Fan, Christian Grimm, Kotdaji Ha, Meiqin Hu, Sairam V. Jabba, Sven‐Eric Jordt, David Julius, Kristopher T. Kahle, Michael X. Zhu

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