TRPC5

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).

The TRPC subfamily consists of seven members (TRPC1-7). Like the other members of the TRP superfamily, they contain six transmembrane domains with an ion channel between the fifth and sixth domains. The N and C termini of TRPCs harbor a variety of functional domains including ankyrin repeats, calmodulin binding sites, phosphorylation sites and sites of interaction with other molecules such as Homer, Orai, STIM1, Junctate, IP3 receptor (IP3R).

Activation of the channels by the natural product (-)-englerin A (EA), which has high potency and selectivity for TRPC4/5, inhibits tumor growth of renal cancer cells by increasing Ca2+ influx (Akbulut et al. 2015). Other activators include riluzole, BTD, and the glucocorticoid methylprednisolone.

Inhibitors of TRPC4/5 are mostly used to treat renal diseases such as focal segmental glomerulosclerosis (FSGS). Other compounds are currently undergoing clinical trials.

Recently, a new class of small-molecule modulators has been identified that are selective for TRPC4/5 and are built on a piperazinone/pyridazinone scaffold (Yu et al. 2019).

1. Akbulut Y (2015) (-)-Englerin A is a Potent and Selective Activator of TRPC4 and TRPC5 Calcium Channels. Angew Chem. Int Ed 54: 3787-3791.
2. Freichel M et al (2001) Lack of an endothelial store-operated Ca2+ current impairs agonist-dependent vasorelaxation in TRP4-/- mice. Nat Cell Biol 3:121-127.
3. Jeon JP et al. (2012) Selective Gα iSubunits as Novel Direct Activators of Transient Receptor Potential Canonical (TRPC)4 and TRPC5 Channels. J Biol Chem 287: 17029-17039.
4. Kim H et al. (2012) The roles of G proteins in the activation of TRPC4 and TRPC5 transient receptor potential channels. Channels (Austin) 6: 333-343.
5. Kim J (2019) TRPC1 as a negative regulator for TRPC4 and TRPC5 channels Pflugers Arch 471:1045-1053.
6. Nilius B et al (2011) The transient receptor potential family of ion channels. Genome Biol 12:218.
7. Human Protein Atlas Information: (https://www.proteinatlas.org/ENSG00000133107-TRPC4/tissue)
8. Lee KP et al. (2010) STIM1-dependent and STIM1-independent Function of Transient Receptor Potential Canonical (TRPC) Channels Tunes Their Store-operated Mode. J Biol Chem 285: 38666-38673.
9. Miehe S et al. (2010) The phospholipid-binding protein SESTD1 Is a Novel Regulator of the Transient Receptor Potential Channels TRPC4 and TRPC5. J Biol Chem 285: 12426-12434.
10. Minard A et al. (2018) Remarkable Progress with Small-Molecule Modulation of TRPC1/4/5 Channels: Implications for Understanding the Channels in Health and Disease. Cells 7: 52.
11. Yu M et al (2019) Discovery of a Potent and Selective TRPC5 Inhibitor, Efficacious in a Focal Segmental Glomerulosclerosis Model. ACS Med Chem Lett 10: 1579-1585.
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13. Zhu MX (2005). Multiple roles of calmodulin and other Ca2+-binding proteins in the functional regulation of TRP channels. Ploughman's Arch. 451: 105-115.