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

Abstract

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 α13‐subunits significantly reduced ATII‐mediated TRPC6 activation, whereas siRNAs directed against G protein αq‐subunits did not. By employing Gαq−/− murine embryonic fibroblasts, we were able to dissect Gα12/13‐PLC ε‐mediated from Gαq‐PLCβ‐induced TRPC6 activation using lysophosphatidic acid (LPA) receptor stimulation. Most interestingly, application of LPA resulted in a significantly larger increase in the intracellular Ca2+ concentration ([Ca2+]i) in Gαq−/− cells expressing TRPC6 in comparison to Gαq−/− control cells. Therefore, Gα12/13‐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.