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Store depletion induces G?q-mediated PLC?1 activity to stimulate TRPC1 channels in vascular smooth muscle cells.


ABSTRACT: Depletion of sarcoplasmic reticulum (SR) Ca(2+) stores activates store-operated channels (SOCs) composed of canonical transient receptor potential (TRPC) 1 proteins in vascular smooth muscle cells (VSMCs), which contribute to important cellular functions. We have previously shown that PKC is obligatory for activation of TRPC1 SOCs in VSMCs, and the present study investigates if the classic phosphoinositol signaling pathway involving G?q-mediated PLC activity is responsible for driving PKC-dependent channel gating. The G-protein inhibitor GDP-?-S, anti-G?q antibodies, the PLC inhibitor U73122, and the PKC inhibitor GF109203X all inhibited activation of TRPC1 SOCs, and U73122 and GF109203X also reduced store-operated PKC-dependent phosphorylation of TRPC1 proteins. Three distinct SR Ca(2+) store-depleting agents, 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester, cyclopiazonic acid, and N,N,N',N'-tetrakis(2-pyridylmethyl)ethane-1,2-diamineed, induced translocations of the fluorescent biosensor GFP-PLC?1-PH from the cell membrane to the cytosol, which were inhibited by U73122. Knockdown of PLC?1 with small hairpin RNA reduced both store-operated PLC activity and stimulation of TRPC1 SOCs. Immunoprecipitation studies and proximity ligation assays revealed that store depletion induced interactions between TRPC1 and G?q, and TRPC1 and PLC?1. We propose a novel activation mechanism for TRPC1 SOCs in VSMCs, in which store depletion induces formation of TRPC1-G?q-PLC?1 complexes that lead to PKC stimulation and channel gating.

SUBMITTER: Shi J 

PROVIDER: S-EPMC4714548 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Store depletion induces Gαq-mediated PLCβ1 activity to stimulate TRPC1 channels in vascular smooth muscle cells.

Shi Jian J   Miralles Francesc F   Birnbaumer Lutz L   Large William A WA   Albert Anthony P AP  

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20151014 2


Depletion of sarcoplasmic reticulum (SR) Ca(2+) stores activates store-operated channels (SOCs) composed of canonical transient receptor potential (TRPC) 1 proteins in vascular smooth muscle cells (VSMCs), which contribute to important cellular functions. We have previously shown that PKC is obligatory for activation of TRPC1 SOCs in VSMCs, and the present study investigates if the classic phosphoinositol signaling pathway involving Gαq-mediated PLC activity is responsible for driving PKC-depend  ...[more]

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