TRPM3
Identifiers
AliasesTRPM3, GON-2, LTRPC3, MLSN2, transient receptor potential cation channel subfamily M member 3
External IDsOMIM: 608961 MGI: 2443101 HomoloGene: 62287 GeneCards: TRPM3
Orthologs
SpeciesHumanMouse
Entrez

80036

226025

Ensembl

ENSG00000083067

ENSMUSG00000052387

UniProt

Q9HCF6

n/a

RefSeq (mRNA)
RefSeq (protein)

n/a

Location (UCSC)Chr 9: 70.53 – 71.45 MbChr 19: 22.12 – 22.97 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Transient receptor potential cation channel subfamily M member 3 is a protein that in humans is encoded by the TRPM3 gene.[5]

Function

The product of this gene belongs to the family of transient receptor potential (TRP) channels.[6] 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.[7] TRPM3 was shown to be activated by the neurosteroid pregnenolone sulfate as well as the synthetic compound CIM0216.

Peripheral heat sensation

TRPM3 is expressed in peripheral sensory neurons of the dorsal root ganglia, and they are activated by high temperatures.[8] Genetic deletion of TRPM3 in mice reduces sensitivity to noxious heat, as well as inflammatory thermal hyperalgesia.[8][9] Inhibitors of TRPM3 were also shown to reduce noxious heat and inflammatory heat hyperalgesia,[10][11][9] as well as reduce heat hyperalgesia and spontaneous pain in nerve injury induced neuropathic pain.[9]

Receptor mediated inhibition

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.[12][13][14] Gβγ was shown to bind to a short α-helical segment of the channel.[15] Receptors that inhibit TRPM3 include opioid receptors[13][16] and GABAB receptors.[12]

TRPM3 in the brain

Mutations in TRPM3 in humans, were recently shown to cause a intellectual disability and epilepsy.[17] The disease associated mutations were shown to increase the sensitivity of the channel to agonists, and heat.[18][19][20]

TRPM3 ligands, activators and modulators

Activators

Channel Blockers

  1. Mefenamic acid[23]
  2. Citrus fruit flavonoids, e.g. naringenin, isosakuranetin and hesperetin, as well as ononetin (a deoxybenzoin).[24]
  3. Primidone, a clinically used antiepileptic medication also directly inhibits TRPM3.[10]

Activity Modulator

See also

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000083067 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000052387 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Clapham DE, Julius D, Montell C, Schultz G (December 2005). "International Union of Pharmacology. XLIX. Nomenclature and structure-function relationships of transient receptor potential channels". Pharmacological Reviews. 57 (4): 427–50. doi:10.1124/pr.57.4.6. PMID 16382100. S2CID 17936350.
  6. ↑ Ramsey IS, Delling M, Clapham DE (2006). "An introduction to TRP channels". Annual Review of Physiology. 68: 619–47. doi:10.1146/annurev.physiol.68.040204.100431. PMID 16460286.
  7. ↑ "Entrez Gene: TRPM3 transient receptor potential cation channel, subfamily M, member 3".
  8. 1 2 3 Vriens J, Owsianik G, Hofmann T, Philipp SE, Stab J, Chen X, et al. (May 2011). "TRPM3 is a nociceptor channel involved in the detection of noxious heat". Neuron. 70 (3): 482–94. doi:10.1016/j.neuron.2011.02.051. PMID 21555074.
  9. 1 2 3 Su, Songxue; Yudin, Yevgen; Kim, Nawoo; Tao, Yuan-Xiang; Rohacs, Tibor (2021-03-17). "TRPM3 Channels Play Roles in Heat Hypersensitivity and Spontaneous Pain after Nerve Injury". The Journal of Neuroscience. 41 (11): 2457–2474. doi:10.1523/JNEUROSCI.1551-20.2020. ISSN 1529-2401. PMC 7984590. PMID 33478988.
  10. 1 2 Krügel U, Straub I, Beckmann H, Schaefer M (May 2017). "Primidone inhibits TRPM3 and attenuates thermal nociception in vivo". Pain. 158 (5): 856–867. doi:10.1097/j.pain.0000000000000846. PMC 5402713. PMID 28106668.
  11. ↑ Straub, Isabelle; Krügel, Ute; Mohr, Florian; Teichert, Jens; Rizun, Oleksandr; Konrad, Maik; Oberwinkler, Johannes; Schaefer, Michael (November 2013). "Flavanones that selectively inhibit TRPM3 attenuate thermal nociception in vivo". Molecular Pharmacology. 84 (5): 736–750. doi:10.1124/mol.113.086843. ISSN 1521-0111. PMID 24006495. S2CID 20522738.
  12. 1 2 Badheka D, Yudin Y, Borbiro I, Hartle CM, Yazici A, Mirshahi T, Rohacs T (August 2017). "Inhibition of Transient Receptor Potential Melastatin 3 ion channels by G-protein βγ subunits". eLife. 6. doi:10.7554/eLife.26147. PMC 5593506. PMID 28829742.
  13. 1 2 Dembla S, Behrendt M, Mohr F, Goecke C, Sondermann J, Schneider FM, et al. (August 2017). "Anti-nociceptive action of peripheral mu-opioid receptors by G-beta-gamma protein-mediated inhibition of TRPM3 channels". eLife. 6. doi:10.7554/eLife.26280. PMC 5593507. PMID 28826482.
  14. ↑ Quallo T, Alkhatib O, Gentry C, Andersson DA, Bevan S (August 2017). "G protein βγ subunits inhibit TRPM3 ion channels in sensory neurons". eLife. 6. doi:10.7554/eLife.26138. PMC 5593501. PMID 28826490.
  15. ↑ Behrendt M, Gruss F, Enzeroth R, Dembla S, Zhao S, Crassous PA, et al. (November 2020). "The structural basis for an on-off switch controlling Gβγ-mediated inhibition of TRPM3 channels". Proceedings of the National Academy of Sciences of the United States of America. 117 (46): 29090–29100. Bibcode:2020PNAS..11729090B. doi:10.1073/pnas.2001177117. PMC 7682392. PMID 33122432.
  16. ↑ Yudin Y, Rohacs T (September 2019). "The G-protein-biased agents PZM21 and TRV130 are partial agonists of μ-opioid receptor-mediated signalling to ion channels". British Journal of Pharmacology. 176 (17): 3110–3125. doi:10.1111/bph.14702. PMC 6692666. PMID 31074038.
  17. ↑ Dyment DA, Terhal PA, Rustad CF, Tveten K, Griffith C, Jayakar P, et al. (October 2019). "De novo substitutions of TRPM3 cause intellectual disability and epilepsy". European Journal of Human Genetics. 27 (10): 1611–1618. doi:10.1038/s41431-019-0462-x. PMC 6777445. PMID 31278393.
  18. ↑ Zhao S, Yudin Y, Rohacs T (April 2020). "Disease-associated mutations in the human TRPM3 render the channel overactive via two distinct mechanisms". eLife. 9. doi:10.7554/eLife.55634. PMC 7255801. PMID 32343227.
  19. ↑ Van Hoeymissen E, Held K, Nogueira Freitas AC, Janssens A, Voets T, Vriens J (May 2020). "Gain of channel function and modified gating properties in TRPM3 mutants causing intellectual disability and epilepsy". eLife. 9. doi:10.7554/eLife.57190. PMC 7253177. PMID 32427099.
  20. ↑ Zhao S, Rohacs T (December 2021). "The newest TRP channelopathy: Gain of function TRPM3 mutations cause epilepsy and intellectual disability". Channels. 15 (1): 386–397. doi:10.1080/19336950.2021.1908781. PMC 8057083. PMID 33853504.
  21. ↑ Wagner TF, Loch S, Lambert S, Straub I, Mannebach S, Mathar I, et al. (December 2008). "Transient receptor potential M3 channels are ionotropic steroid receptors in pancreatic beta cells". Nature Cell Biology. 10 (12): 1421–30. doi:10.1038/ncb1801. PMID 18978782. S2CID 19925356.
  22. ↑ Held K, Kichko T, De Clercq K, Klaassen H, Van Bree R, Vanherck JC, et al. (March 2015). "Activation of TRPM3 by a potent synthetic ligand reveals a role in peptide release". Proceedings of the National Academy of Sciences of the United States of America. 112 (11): E1363-72. Bibcode:2015PNAS..112E1363H. doi:10.1073/pnas.1419845112. PMC 4371942. PMID 25733887.
  23. ↑ Klose C, Straub I, Riehle M, Ranta F, Krautwurst D, Ullrich S, et al. (April 2011). "Fenamates as TRP channel blockers: mefenamic acid selectively blocks TRPM3". British Journal of Pharmacology. 162 (8): 1757–69. doi:10.1111/j.1476-5381.2010.01186.x. PMC 3081119. PMID 21198543.
  24. ↑ Straub I, Mohr F, Stab J, Konrad M, Philipp SE, Oberwinkler J, Schaefer M (April 2013). "Citrus fruit and fabacea secondary metabolites potently and selectively block TRPM3". British Journal of Pharmacology. 168 (8): 1835–50. doi:10.1111/bph.12076. PMC 3623054. PMID 23190005.
  25. ↑ Hossain Saad Md Zubayer, Xiang Liuruimin, Liao Yan-Shin, Reznikov Leah R., Du Jianyang (2021). "The Underlying Mechanism of Modulation of Transient Receptor Potential Melastatin 3 by protons". Frontiers in Pharmacology. 12:632711: 632711. doi:10.3389/fphar.2021.632711. PMC 7884864. PMID 33603674.{{cite journal}}: CS1 maint: multiple names: authors list (link)

Further reading

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