TRPM5

TRPM5 is the acronym for Transient Receptor Potential Cation Channel, Subfamily M, Member 5. Melastatin-related Transient Receptor Potential (TRP) channel is a non-selective cation channel. TRPM5 is expressed in chemosensitive tissues from solitary chemosensory cells to taste receptor cells and in pancreatic β-cells (Vennekens R et al. 2018).

TRP channels are phylogenetically early signaling pathways (they can already be detected in yeast cells). The first TRP channel was identified in 1989 in connection with visual perception in Drosophila melanogaster. In a Drosophila mutant (trp343), it was shown that its photoreceptors responded to light stimuli only with a transient, i.e. rapidly inactivating, membrane current. In the non-mutated wild type, however, the current flow persisted as long as light hit the photoreceptor. The mutant protein -TRP- was cloned in 1989. Thus, the name "transient receptor potential" - TRP- refers to the description of a phenotype of a mutant of the fruit fly Drosophila melanogaster. TRP channels exert important functions in primary signaling pathways for the regulated influx of Ca2+ into a cell in both vertebrates and non-vertebrates. TRP channels in humans play an important role in the sensation of different types of taste (sweet, bitter, umami) as well as in the perception of pain, heat, warmth or cold, pressure and light. It is believed that some TRP channels in the body behave like microscopic thermosensors. To date, 28 TRP channel genes have been identified in mammals (Nilius B et al. 2011).

TRPMs (except for TRPM4 and TRMP5) are Ca(2+)-permeable cation channels localized predominantly to the plasma membrane. The structural machinery of TRPM channels includes intracellular N- and C-termini, 6 transmembrane segments, and a pore region between segments 5 and 6. The N-terminal domain has a conserved region, and the C-terminal domain contains a TRP motif, a coiled-coil region, and, in some TRPM channels, an enzymatic domain. TRPM3, unlike other TRPM channels, is activated by sphingosine (Farooqi et al. 2011). Its activation triggers a signal transduction cascade of mitogen-activated kinases and stimulus-response transcription factors.

TRPM5 is a voltage-modulated,^{Ca2+-activated}, monovalent cation channel (VCAM) that mediates transient membrane depolarization and plays a central role in taste transduction. TRPM5 is directly activated by the increase in intracellular Ca2+ but, unlike other TRPs, is itself impermeable to calcium ions (see also the further exception for TRPM4) . "Gating" is voltage-dependent and shows rapid activation and deactivation kinetics upon channel stimulation, even with sustained increases in Ca2+ content.

Furthermore, TRPM5 is a highly temperature-sensitive, heat-activated channel that induces a steep increase in inward cation currents at temperatures between 15 and 35 degrees Celsius.

TRPM5 is involved in the perception of taste sensations (Kaske S et al. 2007; Liman ER 2007). Thus, the G protein-coupled taste receptors T1R and T2R initiate a common signaling pathway involving TRPM5 to encode sweet, umami, and bitter taste sensations. Trpm5-/- mice have deficient type II taste perception and show decreased glucose-induced insulin secretion.

Mutations in TRPM5 have been linked to type II diabetes and metabolic syndrome (Vennekens R et al 2018).

TRPM5 agonists: In vitro, the channel is activated by arachidonic acid. Furthermore, steviol glycosides found in the leaves of the Stevia rebaudiana plant have an activating effect. Steviol glycosides thus stimulate glucose-induced insulin secretion from the pancreatic β-cell (Philippaert K et al. (2017) Rutamarin found in Ruta graveolens activates several TRP channels including TRPM5 and TRPV1, while inhibiting the activity of TRPM8 (Mancuso G et al. (2015).

TRPM5 antagonists: Selective blocking agents of TRPM5 ion channels can be used to identify TRPM5 currents in primary cells. However, most identified compounds show poor selectivity between TRPM4 and TRPM5 or other ion channels. TPPO (triphenylphosphine oxide) is the most selective blocker of TRPM5 (Palmer RK et al (2010). Furthermore, the pharmaceuticals ketoconazole, flufenamic acid, clotrimazole inhibit the activity of TPRM5 (Ullrich ND et al 2005). Nicotine also inhibits the TRPM5 channel. Inhibition of TRPM5 may explain the loss of taste often observed in people with smoking habits (Gees M et al. (2014). The channel is blocked by extracellular pH shifts into the acidic milieu range.

1. Farooqi A et al. (2011) TRPM channels: same ballpark, different players, and different rules in immunogenetics. Immunogenetics 63: 773-787
2. Gees M et al. (2014) Differential effects of bitter compounds on the taste transduction channels TRPM5 and IP3 receptor type 3. Chemical Senses 39: 295-311.
3. Kaske S et al. (2007) TRPM5, a taste-signaling transient receptor potential ion channel, is a ubiquitous signaling component in chemosensory cells. BMC Neuroscience 8: 49.
4. Liman ER (2007) TRPM5 and taste transduction. Handb Exp Pharmacol179:287-298.
5. Mancuso G et al. (2015) Phytochemicals from Ruta graveolens Activate TAS2R Bitter Taste Receptors and TRP Channels Involved in Gustation and Nociception. Molecules 20: 18907-1822.
6. Mathar I et al (2014) Handb Exp Pharmacol 222:461-487.
7. Nilius B et al (2011) The transient receptor potential family of ion channels. Genome Biol 12:218.
8. Palmer RK et al. (2010) Triphenylphosphine oxide is a potent and selective inhibitor of the transient receptor potential melastatin-5 ion channel. Assay and Drug Development Technologies 8: 703-713.
9. Philippaert K et al. (2017) Steviol glycosides enhance pancreatic beta-cell function and taste sensation by potentiation of TRPM5 channel activity. Nature Communications 8: 14733.
10. Ullrich ND et al (2005) Comparison of functional properties of the Ca2+-activated cation channels TRPM4 and TRPM5 from mice. Cell Calcium 37: 267-278.
11. Vennekens R et al (2018) TRPM5 in the battle against diabetes and obesity. Acta Physiol (Oxf) doi: 10.1111/apha.12949.