PLCε‐dependent activation of TRPC6 channels in kidney podocytes, murine embryonic fibroblasts (MEFs) and human embryonic kidney cells (HEK 293): A general mechanism?

Gain of function mutations of TRPC6 as well as loss of function mutations in PLC ε were identified in patients suffering from focal segmental glomerular sclerosis (FSGS), a disease displaying increasing proteinuria due to a defect in the glomerular filtration process of the kidney. Along these lines, we have previously shown that PLC ε physically interacts and activates TRPC6 via production of diacylglycerol (DAG) in kidney podocytes to increase the barrier function of the glomerular slit diaphragm. Moreover, down‐regulation of G‐protein α 13 ‐subunits significantly reduced ATII‐mediated TRPC6 activation, whereas siRNAs directed against G protein α q ‐subunits did not. By employing Gα q −/− murine embryonic fibroblasts, we were able to dissect Gα 12/13 ‐PLC ε‐mediated from Gα q ‐PLCβ‐induced TRPC6 activation using lysophosphatidic acid (LPA) receptor stimulation. Most interestingly, application of LPA resulted in a significantly larger increase in the intracellular Ca 2+ concentration ([Ca 2+ ] i ) in Gα q −/− cells expressing TRPC6 in comparison to Gα q −/− control cells. Therefore, Gα 12/13 ‐mediated activation of PLC ε via RhoA leading to TRPC6‐induced cation influx might be a general, but commonly‐ignored signal transduction pathway in many cell types.