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PLCε‐dependent activation of TRPC6 channels in kidney podocytes, murine embryonic fibroblasts (MEFs) and human embryonic kidney cells (HEK 293): A general mechanism?
Author(s) -
Dietrich Alexander,
Kalwa Hermann,
Mayer Tim,
Fahlbusch Meike,
Storch Ursula,
Offermanns Stefan,
Smrcka Allan,
Hildebrandt Friedhelm,
Gudermann Thomas
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.lb622
Subject(s) - trpc6 , hek 293 cells , microbiology and biotechnology , diacylglycerol kinase , rhoa , kidney , chemistry , trpc3 , signal transduction , medicine , biology , receptor , endocrinology , trpc , protein kinase c , transient receptor potential channel , biochemistry
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.