TRPM3

TRPM3
Identifiers
Aliases	TRPM3, GON-2, LTRPC3, MLSN2, transient receptor potential cation channel subfamily M member 3
External IDs	OMIM: 608961; MGI: 2443101; HomoloGene: 62287; GeneCards: TRPM3; OMA:TRPM3 - orthologs
Gene location (Human) Chr. Chromosome 9 (human)[1] Band 9q21.12-q21.13 Start 70,529,060 bp[1] End 71,446,904 bp[1]
Gene location (Mouse) Chr. Chromosome 19 (mouse)[2] Band 19|19 B Start 22,116,410 bp[2] End 22,972,774 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in retinal pigment epithelium dorsal motor nucleus of vagus nerve internal globus pallidus buccal mucosa cell sural nerve inferior olivary nucleus external globus pallidus cerebellar vermis superior vestibular nucleus pars compacta Top expressed in retinal pigment epithelium ciliary body Epithelium of choroid plexus epithelium of lens otolith organ utricle lobe of cerebellum median eminence cerebellar vermis superior colliculus More reference expression data BioGPS More reference expression data
Gene ontology Molecular function ion channel activity calcium activated cation channel activity cation channel activity calcium channel activity Cellular component integral component of membrane plasma membrane membrane Biological process detection of temperature stimulus ion transport protein tetramerization sensory perception of temperature stimulus calcium ion transport ion transmembrane transport cation transport transmembrane transport calcium ion transmembrane transport Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 80036 226025 Ensembl ENSG00000083067 ENSMUSG00000052387 UniProt Q9HCF6 n/a RefSeq (mRNA) NM_001007470 NM_001007471 NM_020952 NM_024971 NM_206944 NM_206945 NM_206946 NM_206947 NM_206948 NM_001366141 NM_001366142 NM_001366143 NM_001366144 NM_001366145 NM_001366146 NM_001366147 NM_001366148 NM_001366149 NM_001366150 NM_001366151 NM_001366152 NM_001366153 NM_001366154 NM_001035239 NM_001035240 NM_001035241 NM_001035242 NM_001035243 NM_001035244 NM_001035245 NM_001035246 NM_177341 NM_001362487 NM_001362488 NM_001362489 NM_001362490 NM_001362491 NM_001362496 NM_001362497 NM_001362498 NM_001362499 NM_001362500 NM_001362501 NM_001362502 NM_001362503 NM_001362504 NM_001362505 NM_001362506 NM_001362507 NM_001362508 NM_001362511 NM_001362512 NM_001362513 RefSeq (protein) NP_001007471 NP_001007472 NP_066003 NP_079247 NP_996827 NP_996828 NP_996829 NP_996830 NP_996831 NP_001353070 NP_001353071 NP_001353072 NP_001353073 NP_001353074 NP_001353075 NP_001353076 NP_001353077 NP_001353078 NP_001353079 NP_001353080 NP_001353081 NP_001353082 NP_001353083 n/a Location (UCSC) Chr 9: 70.53 – 71.45 Mb Chr 19: 22.12 – 22.97 Mb PubMed search [3] [4]
Wikidata
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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 Ca^2+ 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 Ca^2+ 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 GABA_B 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

• Heat[8]
• Pregnenolone Sulfate[21]
• CIM-0216[22]

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

• pH [25]

See also

• TRPM
• TRPM3-related neurodevelopmental disorders

References

1. GRCh38: Ensembl release 89: ENSG00000083067 – Ensembl, May 2017
2. 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. 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. 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. 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. 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. 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.

Further reading

• Oberwinkler J, Phillipp SE (2007). "TRPM3". Transient Receptor Potential (TRP) Channels. Handbook of Experimental Pharmacology. Vol. 179. pp. 253–67. doi:10.1007/978-3-540-34891-7_15. ISBN 978-3-540-34889-4. PMID 17217062.
• Harteneck C, Reiter B (February 2007). "TRP channels activated by extracellular hypo-osmoticity in epithelia". Biochemical Society Transactions. 35 (Pt 1): 91–5. doi:10.1042/BST0350091. PMID 17233610.
• Held K, Voets T, Vriens J (2014). "TRPM3 in temperature sensing and beyond". Temperature. 2 (2): 201–13. doi:10.4161/23328940.2014.988524. PMC 4844244. PMID 27227024.
• Islam MS, ed. (2011). Transient Receptor Potential Channels. Advances in Experimental Medicine and Biology. Vol. 704. New York: Springer Science+Business Media. doi:10.1007/978-94-007-0265-3. ISBN 978-94-007-0265-3. ISSN 2214-8019. OCLC 710148029. Archived from the original on 2010-09-11. Retrieved 2010-10-29.

External links

• TRPM3+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

This article incorporates text from the United States National Library of Medicine, which is in the public domain.