TRPM3

Function

The product of this gene belongs to the family of transient receptor potential (TRP) channels. 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. 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. Genetic deletion of TRPM3 in mice reduces sensitivity to noxious heat, as well as inflammatory thermal hyperalgesia. Inhibitors of TRPM3 were also shown to reduce noxious heat and inflammatory heat hyperalgesia, as well as reduce heat hyperalgesia and spontaneous pain in nerve injury induced neuropathic pain.

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. Gβγ was shown to bind to a short α-helical segment of the channel. Receptors that inhibit TRPM3 include opioid receptors and GABAB receptors.

TRPM3 in the brain

Mutations in TRPM3 in humans, were recently shown to cause an intellectual disability and epilepsy. The disease associated mutations were shown to increase the sensitivity of the channel to agonists, and heat.

TRPM3 ligands, activators and modulators

Activators

• Heat
• Pregnenolone Sulfate
• CIM-0216

Channel Blockers

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

Activity Modulator

• pH

References

References

1. (December 2005). "International Union of Pharmacology. XLIX. Nomenclature and structure-function relationships of transient receptor potential channels". Pharmacological Reviews.
2. (2006). "An introduction to TRP channels". Annual Review of Physiology.
3. "Entrez Gene: TRPM3 transient receptor potential cation channel, subfamily M, member 3".
4. (May 2011). "TRPM3 is a nociceptor channel involved in the detection of noxious heat". Neuron.
5. (2021-03-17). "TRPM3 Channels Play Roles in Heat Hypersensitivity and Spontaneous Pain after Nerve Injury". The Journal of Neuroscience.
6. (November 2013). "Flavanones that selectively inhibit TRPM3 attenuate thermal nociception in vivo". Molecular Pharmacology.
7. (August 2017). "Inhibition of Transient Receptor Potential Melastatin 3 ion channels by G-protein βγ subunits". eLife.
8. (August 2017). "Anti-nociceptive action of peripheral mu-opioid receptors by G-beta-gamma protein-mediated inhibition of TRPM3 channels". eLife.
9. (August 2017). "G protein βγ subunits inhibit TRPM3 ion channels in sensory neurons". eLife.
10. (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.
11. (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.
12. (October 2019). "De novo substitutions of TRPM3 cause intellectual disability and epilepsy". European Journal of Human Genetics.
13. (April 2020). "Disease-associated mutations in the human TRPM3 render the channel overactive via two distinct mechanisms". eLife.
14. (May 2020). "Gain of channel function and modified gating properties in TRPM3 mutants causing intellectual disability and epilepsy". eLife.
15. (December 2021). "The newest TRP channelopathy: Gain of function TRPM3 mutations cause epilepsy and intellectual disability". Channels.
16. (December 2008). "Transient receptor potential M3 channels are ionotropic steroid receptors in pancreatic beta cells". Nature Cell Biology.
17. (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.
18. (April 2011). "Fenamates as TRP channel blockers: mefenamic acid selectively blocks TRPM3". British Journal of Pharmacology.
19. (April 2013). "Citrus fruit and fabacea secondary metabolites potently and selectively block TRPM3". British Journal of Pharmacology.
20. (May 2017). "Primidone inhibits TRPM3 and attenuates thermal nociception in vivo". Pain.
21. (2021). "The Underlying Mechanism of Modulation of Transient Receptor Potential Melastatin 3 by protons". Frontiers in Pharmacology.