TRPM5

Function

TRPM5 is a calcium-activated non-selective cation channel that induces depolarization upon increases in intracellular calcium, it is a signal mediator in chemosensory cells. Channel activity is initiated by a rise in the intracellular calcium, and the channel permeates monovalent cations as K+ and Na+. TRPM5 is a key component of taste transduction in the gustatory system of bitter, sweet and umami tastes being activated by high levels of intracellular calcium. It has also been targeted as a possible contributor to fat taste signaling. The calcium dependent opening of TRPM5 produces a depolarizing generator potential which leads to an action potential.

TRPM5 is expressed in pancreatic β-cells where it is involved in the signaling mechanism for insulin secretion. The potentiation of TRPM5 in the β-cells leads to increased insulin secretion and protects against the development of type 2 diabetes in mice. Further expression of TRPM5 can be found in tuft cells, solitary chemosensory cells and several other cell types in the body that have a sensory role.

Drugs modulating TRPM5

The role of TRPM5 in the pancreatic β-cell makes it a target for the development of novel antidiabetic therapies.

Agonists

• Steviol glycosides, the sweet compounds in the leaves of the Stevia rebaudiana plant, potentiate the calcium-induced activity of TRPM5. In this way they stimulate the glucose-induced insulin secretion from the pancreatic β-cell.
• Rutamarin, a phytochemical found in Ruta graveolens has been identified as an activator of several TRP channels, including TRPM5 and TRPV1 and inhibits the activity of TRPM8.

Antagonists

Selective blocking agents of TRPM5 ion channels can be used to identify TRPM5 currents in primary cells. Most identified compounds show, however, a poor selectivity between TRPM4 and TRPM5 or other ion channels.

• TPPO or TriPhenylPhosphineOxide is the most selective blocker of TRPM5 however, its application suffers due to a poor solubility.
• Ketoconazole is an antifungal drug that inhibits TRPM5 activity.
• Flufenamic Acid is an NSAID drug that inhibits the activity of TRPM5 or TRPM4.
• Clotrimazole is an antifungal drug and reduces the currents through TRPM5.
• Nicotine inhibits the TRPM5 channel. Through the inhibition of TRPM5, the taste loss observed in people with a smoking habit can be explained.

References

References

1. (January 2000). "Identification and characterization of MTR1, a novel gene with homology to melastatin (MLSN1) and the trp gene family located in the BWS-WT2 critical region on chromosome 11p15.5 and showing allele-specific expression". Human Molecular Genetics.
2. (December 2005). "International Union of Pharmacology. XLIX. Nomenclature and structure-function relationships of transient receptor potential channels". Pharmacological Reviews.
3. (September 2011). "Accumulating evidence supports a taste component for free fatty acids in humans". Physiology & Behavior.
4. (June 2011). "Transient receptor potential channel type M5 is essential for fat taste". The Journal of Neuroscience.
5. (August 2010). "The cell biology of taste". The Journal of Cell Biology.
6. (March 2010). "Loss of high-frequency glucose-induced Ca2+ oscillations in pancreatic islets correlates with impaired glucose tolerance in Trpm5-/- mice". Proceedings of the National Academy of Sciences of the United States of America.
7. (March 2017). "Steviol glycosides enhance pancreatic beta-cell function and taste sensation by potentiation of TRPM5 channel activity". Nature Communications.
8. (July 2007). "TRPM5, a taste-signaling transient receptor potential ion-channel, is a ubiquitous signaling component in chemosensory cells". BMC Neuroscience.
9. (1 January 2015). "Chapter 19 - Transient Receptor Potential (TRP) Cation Channels in Diabetes". TRP Channels as Therapeutic Targets.
10. (October 2015). "Phytochemicals from Ruta graveolens Activate TAS2R Bitter Taste Receptors and TRP Channels Involved in Gustation and Nociception". Molecules.
11. (December 2010). "Triphenylphosphine oxide is a potent and selective inhibitor of the transient receptor potential melastatin-5 ion channel". Assay and Drug Development Technologies.
12. (January 2018). "2+-Activated Monovalent Cation-Selective Channels". SLAS Discovery: Advancing Life Sciences R & D.
13. (March 2005). "Comparison of functional properties of the Ca2+-activated cation channels TRPM4 and TRPM5 from mice". Cell Calcium.
14. (May 2014). "Differential effects of bitter compounds on the taste transduction channels TRPM5 and IP3 receptor type 3". Chemical Senses.