TRPC6

TRPC6 is the acronym for Transient Receptor Potential Cation Channel Subfamily C Member 6D, a receptor-activated (redox-regulated) Ca2+-permeable, non-selective cation channel that contributes to homeostasis of cytosolic free Ca2+ concentration.TRPC6 is encoded by the gene of the same name located on chromosome 11q22.1. TRPC6 channels are directly activated by the second messenger diacylglycerol (DAG) and regulated by specific tyrosine or serine phosphorylation. Extracellular Ca2+ has inhibitory effects, whereas Ca2+/calmodulin acting from the intracellular side has potentiating effects on channel activity. Unlike other TRPCs, TRPC6 is not activated by low intracellular calcium levels (Dietrich A et al. 2007).

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).

TRPC is the acronym for "transient receptor potential cation channel, subfamily C". TRPCs represent a group of receptor-operated, calcium-permeable, non-selective cation channels of the TRP superfamily. Structurally, members of this family possess a number of similar features, including 3 or 4 ankyrin repeats near the N-terminus and a TRP box motif at the proximal C-terminus. Cryogenic electron microscopy was used to visualize several high-resolution structures of TRPC channels with channel structures. The TRPCs are permeable to cations, although the prevalence of calcium over sodium is variable between different members. In general, TRPC channels can be activated by phospholipase C, although some members, especially TRPC6, are activated by diacylglycerol.

TRPC6 is expressed in the brain, in smooth muscle-containing tissues, in the lung and kidney, and in immune and blood cells (Dietrich A et al. 2007).

TRPC6 and TRPC3 channels play a role in cardiac hypertrophy and vascular disease. TRPC3 is upregulated in the atria of patients with atrial fibrillation (AF).

Lung: Pulmonary endothelial cell permeability depends on TRPC6 and induces the formation of ischemia-reperfusion edema in the lung (Dietrich A et al. (2014). In primary lung fibroblasts, TRPC6 is expressed after application of transforming growth factor beta (TGF-β) and promotes myofibroblast differentiation and the formation of lung fibrosis. Furthermore, TRPC6 channels exert a disease-promoting stimulatory effect in pulmonary arterial hypertension (PAH) (Yamamura H et al. 2020). TRPC6 regulates the oxidative stress-mediated Ca2+ cascade in human bronchial epithelial cell lines. Increased expression of TRPC6 leads to activation of the ERK pathway and inflammatory response. TRPC6 could thus become a potential target for the treatment of airway inflammatory diseases induced by oxidative stress. (Chen Q et al 2020)

Kidney: Evidence shows that TRPC6 is expressed by podocytes of the renal glomerula. Alterations in TRPC6 function may impair the cytoskeletal adaptive response of podocytes to injury and eventually lead to progressive damage (Dietrich A et al 2007).

Brain: The extent to which TRPC6 plays an etiopathogentic role in Alzheimer` s disease remains to be seen. The Ca2+-dependent pharmacological action of TRPC6 is associated with stabilization and protection of excitatory synapses. Both down-regulation and up-regulation of TRPC6 channel functions have been observed in models of Alzheimer's disease and brain ischemia. (Prikhodko V et al 2020).

TRPC6 mutations: In 2005, two research groups independently reported that the TRPC6 gene is mutated in a subset of patients with the autosomal dominant form of FSGS. This disease is caused by a missense mutation in TRPC6. Subsequently, other families with various TRPC6 mutations have been reported in both adults and children. The few studies published to date suggest that TRPC6 mutations account for 3-7% of cases with familial adult-onset FSGS. Affected individuals typically present with high-grade proteinuria.

The involvement of the TRPC6 channel in well-studied signaling pathways and its importance in the impact of genes on human disease make it a potential target for drug therapy (Moran M et al. 2011).

1. Chen Q et al (2020) TRPC6-dependent Ca2+ signaling mediates airway inflammation in response to oxidative stress via ERK pathway. Cell Death Dis 11: 170
2. Fowler MA et al (2007) Corticolimbic expression of TRPC4 and TRPC5 channels in the rodent brain. PLoS ONE 2: e573.
3. Boulay G et al (1999) Modulation of Ca(2+) entry by polypeptides of the inositol 1,4, 5-trisphosphate receptor (IP3R) that bind transient receptor potential (TRP): evidence for roles of TRP and IP3R in store depletion-activated Ca(2+) entry. Proc Natl Acad Sci. U.S.A. 96: 14955-14960
4. Dietrich A et al (2007) TRPC6. Handb Exp Pharmacol179:125-141.
5. Dietrich A et al. (2014) TRPC6: physiological function and pathophysiological relevance. Handb Exp Pharmacol 222:157-188.
6. Hofmann K et al. (2017) Classical transient receptor potential (TRPC6) channels support myofibroblast differentiation and development of experimental pulmonary fibrosis. Biochem Biophys Acta 1863: 560-568.
7. Lessard CB et al. (2005) The overexpression of presenilin2 and Alzheimer's disease-linked presenilin2 variants influences TRPC6-enhanced Ca2+ entry into HEK293 cells. Cell Signal 17: 437-445.
8. Nilius B et al (2011) The transient receptor potential family of ion channels. Genome Biol 12:218.
9. Nilius B et al. 2007). Transient receptor potential cation channels in disease. Physiol Rev 87: 165-217.
10. Prikhodko V et al. (2020) Potential drug candidates to treat TRPC6 channel deficiencies in the pathophysiology of Alzheimer's disease and brain ischemia. Cells 9:2351
11. Rowell J et al (2010) TRP-ing up heart and vessels: canonical transient receptor potentials and cardiovascular disease. Journal of Cardiovascular Translational Research3: 516-524.
12. Yamamura H et al. (2020) Pathophysiological roles of TRPC6 channels in pulmonary arterial hypertension. Nihon Yakurigaku Zasshi 155:230-235.