TRPC6: physiological function and pathophysiological relevance

TRPC6 is a non-selective cation channel 6 times more permeable to Ca(2+) than to Na(+). Channel homotetramers heterologously expressed have a characteristic doubly rectifying current-voltage relationship and are directly activated by the second messenger diacylglycerol (DAG). TRPC6 proteins are also regulated by specific tyrosine or serine phosphorylation and phosphoinositides. Given its specific expression pattern, TRPC6 is likely to play a number of physiological roles which are confirmed by the analysis of a Trpc6 (-/-) mouse model. In smooth muscle Na(+) influx through TRPC6 channels and activation of voltage-gated Ca(2+) channels by membrane depolarisation is the driving force for contraction. Permeability of pulmonary endothelial cells depends on TRPC6 and induces ischaemia-reperfusion oedema formation in the lungs. TRPC6 was also identified as an essential component of the slit diaphragm architecture of kidney podocytes and plays an important role in the protection of neurons after cerebral ischaemia. Other functions especially in immune and blood cells remain elusive. Recently identified TRPC6 blockers may be helpful for therapeutic approaches in diseases with highly activated TRPC6 channel activity.