TRPM3

The product of this gene belongs to the family of transient receptor potential (TRP) channels.{{cite journal | vauthors = Ramsey IS, Delling M, Clapham DE | title = An introduction to TRP channels | journal = Annual Review of Physiology | volume = 68 | pages = 619–647 | date = 2006 | pmid = 16460286 | doi = 10.1146/annurev.physiol.68.040204.100431 }} TRP channels are Ca²⁺ permeable non-selective cation channels that play roles in a wide variety of physiological processes, including calcium signaling, heat and cold sensation, calcium and magnesium homeostasis. TRPMs mediates sodium and calcium entry, which induces depolarization and a cytoplasmic Ca²⁺ signal. Alternatively spliced transcript variants encoding different isoforms have been -identified.{{cite web | title = Entrez Gene: TRPM3 transient receptor potential cation channel, subfamily M, member 3 | url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=80036 }}

TRPM3 was shown to be activated by the neurosteroid pregnenolone sulfate as well as the synthetic compound CIM0216.

TRPM3 is expressed in peripheral sensory neurons of the dorsal root ganglia, and they are activated by high temperatures.{{cite journal | vauthors = Vriens J, Owsianik G, Hofmann T, Philipp SE, Stab J, Chen X, Benoit M, Xue F, Janssens A, Kerselaers S, Oberwinkler J, Vennekens R, Gudermann T, Nilius B, Voets T | title = TRPM3 is a nociceptor channel involved in the detection of noxious heat | journal = Neuron | volume = 70 | issue = 3 | pages = 482–494 | date = May 2011 | pmid = 21555074 | doi = 10.1016/j.neuron.2011.02.051 | doi-access = free }} Genetic deletion of TRPM3 in mice reduces sensitivity to noxious heat, as well as inflammatory thermal hyperalgesia.{{Cite journal | vauthors = Su S, Yudin Y, Kim N, Tao YX, Rohacs T | title = TRPM3 Channels Play Roles in Heat Hypersensitivity and Spontaneous Pain after Nerve Injury | journal = The Journal of Neuroscience | volume = 41 | issue = 11 | pages = 2457–2474 | date = 2021-03-17 | pmid = 33478988 | pmc = 7984590 | doi = 10.1523/JNEUROSCI.1551-20.2020 | issn = 1529-2401 }} Inhibitors of TRPM3 were also shown to reduce noxious heat and inflammatory heat hyperalgesia,{{Cite journal | vauthors = Straub I, Krugel U, Mohr F, Teichert J, Rizun O, Konrad M, Oberwinkler J, Schaefer M | title = Flavanones that selectively inhibit TRPM3 attenuate thermal nociception in vivo | journal = Molecular Pharmacology | volume = 84 | issue = 5 | pages = 736–750 | date = November 2013 | pmid = 24006495 | doi = 10.1124/mol.113.086843 | issn = 1521-0111 | s2cid = 20522738 }} as well as reduce heat hyperalgesia and spontaneous pain in nerve injury induced neuropathic pain.

TRPM3 is robustly inhibited by the activation of cell surface receptors that couple to inhibitory heterotrimeric G-proteins (Gi) via direct binding of the Gβγ subunit of the G-protein to the channel.{{cite journal | vauthors = Badheka D, Yudin Y, Borbiro I, Hartle CM, Yazici A, Mirshahi T, Rohacs T | title = Inhibition of Transient Receptor Potential Melastatin 3 ion channels by G-protein βγ subunits | journal = eLife | volume = 6 | date = August 2017 | pmid = 28829742 | pmc = 5593506 | doi = 10.7554/eLife.26147 | doi-access = free }}{{cite journal | vauthors = Dembla S, Behrendt M, Mohr F, Goecke C, Sondermann J, Schneider FM, Schmidt M, Stab J, Enzeroth R, Leitner MG, Nuñez-Badinez P, Schwenk J, Nürnberg B, Cohen A, Philipp SE, Greffrath W, Bünemann M, Oliver D, Zakharian E, Schmidt M, Oberwinkler J | title = Anti-nociceptive action of peripheral mu-opioid receptors by G-beta-gamma protein-mediated inhibition of TRPM3 channels | journal = eLife | volume = 6 | date = August 2017 | pmid = 28826482 | pmc = 5593507 | doi = 10.7554/eLife.26280 | doi-access = free }}{{cite journal | vauthors = Quallo T, Alkhatib O, Gentry C, Andersson DA, Bevan S | title = G protein βγ subunits inhibit TRPM3 ion channels in sensory neurons | journal = eLife | volume = 6 | date = August 2017 | pmid = 28826490 | pmc = 5593501 | doi = 10.7554/eLife.26138 | doi-access = free }} Gβγ was shown to bind to a short α-helical segment of the channel.{{cite journal | vauthors = Behrendt M, Gruss F, Enzeroth R, Dembla S, Zhao S, Crassous PA, Mohr F, Nys M, Louros N, Gallardo R, Zorzini V, Wagner D, Economou A, Rousseau F, Schymkowitz J, Philipp SE, Rohacs T, Ulens C, Oberwinkler J | title = The structural basis for an on-off switch controlling Gβγ-mediated inhibition of TRPM3 channels | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 117 | issue = 46 | pages = 29090–29100 | date = November 2020 | pmid = 33122432 | pmc = 7682392 | doi = 10.1073/pnas.2001177117 | bibcode = 2020PNAS..11729090B | doi-access = free }} Receptors that inhibit TRPM3 include opioid receptors{{cite journal | vauthors = Yudin Y, Rohacs T | title = The G-protein-biased agents PZM21 and TRV130 are partial agonists of μ-opioid receptor-mediated signalling to ion channels | journal = British Journal of Pharmacology | volume = 176 | issue = 17 | pages = 3110–3125 | date = September 2019 | pmid = 31074038 | pmc = 6692666 | doi = 10.1111/bph.14702 }} and GABA_B receptors.

Mutations in TRPM3 in humans, were recently shown to cause a intellectual disability and epilepsy.{{cite journal | vauthors = Dyment DA, Terhal PA, Rustad CF, Tveten K, Griffith C, Jayakar P, Shinawi M, Ellingwood S, Smith R, van Gassen K, McWalter K, Innes AM, Lines MA | title = De novo substitutions of TRPM3 cause intellectual disability and epilepsy | journal = European Journal of Human Genetics | volume = 27 | issue = 10 | pages = 1611–1618 | date = October 2019 | pmid = 31278393 | pmc = 6777445 | doi = 10.1038/s41431-019-0462-x }} The disease associated mutations were shown to increase the sensitivity of the channel to agonists, and heat.{{cite journal | vauthors = Zhao S, Yudin Y, Rohacs T | title = Disease-associated mutations in the human TRPM3 render the channel overactive via two distinct mechanisms | journal = eLife | volume = 9 | date = April 2020 | pmid = 32343227 | pmc = 7255801 | doi = 10.7554/eLife.55634 | doi-access = free }}{{cite journal | vauthors = Van Hoeymissen E, Held K, Nogueira Freitas AC, Janssens A, Voets T, Vriens J | title = Gain of channel function and modified gating properties in TRPM3 mutants causing intellectual disability and epilepsy | journal = eLife | volume = 9 | date = May 2020 | pmid = 32427099 | pmc = 7253177 | doi = 10.7554/eLife.57190 | doi-access = free }}{{cite journal | vauthors = Zhao S, Rohacs T | title = The newest TRP channelopathy: Gain of function TRPM3 mutations cause epilepsy and intellectual disability | journal = Channels | location = Austin, Tex. | volume = 15 | issue = 1 | pages = 386–397 | date = December 2021 | pmid = 33853504 | pmc = 8057083 | doi = 10.1080/19336950.2021.1908781 }}

• Heat
• Pregnenolone Sulfate{{cite journal | vauthors = Wagner TF, Loch S, Lambert S, Straub I, Mannebach S, Mathar I, Düfer M, Lis A, Flockerzi V, Philipp SE, Oberwinkler J | title = Transient receptor potential M3 channels are ionotropic steroid receptors in pancreatic beta cells | journal = Nature Cell Biology | volume = 10 | issue = 12 | pages = 1421–1430 | date = December 2008 | pmid = 18978782 | doi = 10.1038/ncb1801 | s2cid = 19925356 }}
• CIM-0216{{cite journal | vauthors = Held K, Kichko T, De Clercq K, Klaassen H, Van Bree R, Vanherck JC, Marchand A, Reeh PW, Chaltin P, Voets T, Vriens J | title = Activation of TRPM3 by a potent synthetic ligand reveals a role in peptide release | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 112 | issue = 11 | pages = E1363–72 | date = March 2015 | pmid = 25733887 | pmc = 4371942 | doi = 10.1073/pnas.1419845112 | bibcode = 2015PNAS..112E1363H | doi-access = free }}

1. Mefenamic acid{{cite journal | vauthors = Klose C, Straub I, Riehle M, Ranta F, Krautwurst D, Ullrich S, Meyerhof W, Harteneck C | title = Fenamates as TRP channel blockers: mefenamic acid selectively blocks TRPM3 | journal = British Journal of Pharmacology | volume = 162 | issue = 8 | pages = 1757–1769 | date = April 2011 | pmid = 21198543 | pmc = 3081119 | doi = 10.1111/j.1476-5381.2010.01186.x }}
2. Citrus fruit flavonoids, e.g. naringenin, isosakuranetin and hesperetin, as well as ononetin (a deoxybenzoin).{{cite journal | vauthors = Straub I, Mohr F, Stab J, Konrad M, Philipp SE, Oberwinkler J, Schaefer M | title = Citrus fruit and fabacea secondary metabolites potently and selectively block TRPM3 | journal = British Journal of Pharmacology | volume = 168 | issue = 8 | pages = 1835–1850 | date = April 2013 | pmid = 23190005 | pmc = 3623054 | doi = 10.1111/bph.12076 }}
3. Primidone, a clinically used antiepileptic medication also directly inhibits TRPM3.{{cite journal | vauthors = Krügel U, Straub I, Beckmann H, Schaefer M | title = Primidone inhibits TRPM3 and attenuates thermal nociception in vivo | journal = Pain | volume = 158 | issue = 5 | pages = 856–867 | date = May 2017 | pmid = 28106668 | pmc = 5402713 | doi = 10.1097/j.pain.0000000000000846 }}

• pH {{Cite journal | vauthors = Hossain Saad MZ, Xiang L, Liao YS, Reznikov LR, Du J | title = The Underlying Mechanism of Modulation of Transient Receptor Potential Melastatin 3 by protons | journal = Frontiers in Pharmacology | volume = 12:632711 | year = 2021 | pmid = 33603674 | pmc = 7884864 | doi = 10.3389/fphar.2021.632711 | page = 632711 | doi-access = free }}

• TRPM
• TRPM3-related neurodevelopmental disorders

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• {{cite book | vauthors = Oberwinkler J, Phillipp SE | chapter = TRPM3 | title = Transient Receptor Potential (TRP) Channels | volume = 179 | issue = 179 | pages = 253–267 | year = 2007 | pmid = 17217062 | doi = 10.1007/978-3-540-34891-7_15 | series = Handbook of Experimental Pharmacology | isbn = 978-3-540-34889-4 }}
• {{cite journal | vauthors = Harteneck C, Reiter B | title = TRP channels activated by extracellular hypo-osmoticity in epithelia | journal = Biochemical Society Transactions | volume = 35 | issue = Pt 1 | pages = 91–95 | date = February 2007 | pmid = 17233610 | doi = 10.1042/BST0350091 }}
• {{cite journal | vauthors = Held K, Voets T, Vriens J | title = TRPM3 in temperature sensing and beyond | journal = Temperature | location = Austin, Tex. | volume = 2 | issue = 2 | pages = 201–213 | date = 2014 | pmid = 27227024 | pmc = 4844244 | doi = 10.4161/23328940.2014.988524 }}
• {{cite book | veditors = Islam MS | title = Transient Receptor Potential Channels | location = New York | volume = 704 | year = 2011 | doi = 10.1007/978-94-007-0265-3 | url = http://trpbook.islets.se/ | series = Advances in Experimental Medicine and Biology | publisher = Springer Science+Business Media | isbn = 978-94-007-0265-3 | issn = 2214-8019 | oclc = 710148029 | archive-date = 2010-09-11 | access-date = 2010-10-29 | archive-url = https://web.archive.org/web/20100911215402/http://trpbook.islets.se/ | url-status = dead }}

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• {{MeshName|TRPM3+protein,+human}}

{{NLM content}}

{{Ion channels|g4}}

{{Transient receptor potential channel modulators}}

Category:Ion channels

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