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A more recent version of this article appeared on February 3, 2006
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M507681200v1
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Papers In Press, published online ahead of print November 28, 2005
J. Biol. Chem, 10.1074/jbc.M507681200
Submitted on July 15, 2005
Revised on November 23, 2005
Accepted on November 28, 2005

G-protein coupled receptor agonists activate endogenous phospholipase Cepsilon and phospholipase Cbeta 3 in a temporally distinct manner

Grant G. Kelley, Katherine A. Kaproth-Joslin, Sarah E. Reks, Alan V. Smrcka, and Richard J.H. Wojcikiewicz

Medicine Dept., SUNY Upstate Medical University, Syracuse, NY 13210

Corresponding Author: kelleyg{at}upstate.edu

Phospholipase Cepsilon (PLCepsilon ) is one of the newest members of the phosphatidylinositol-specific phospholipase C (PLC) family. Previous studies have suggested that G-protein coupled receptors (GPCRs) stimulate phosphoinositide (PI) hydrolysis by activating PLCbeta isoforms through Gq family G proteins and Gbeta gamma subunits. Using RNA interference to knockdown PLC isoforms, we demonstrate that the GPCR agonists endothelin (ET-1), lysophosphatidic acid (LPA), and thrombin, acting through endogenous receptors, couple to both endogenous PLCepsilon and the PLCbeta isoform, PLCbeta 3, in Rat-1 fibroblasts. Examination of the temporal activation of these PLC isoforms, however, reveals agonist- and isoform-specific profiles. PLCbeta 3 is activated acutely within the first min of ET-1, LPA or thrombin stimulation but does not contribute to sustained PI hydrolysis induced by LPA or thrombin and accounts for only part of ET-1 sustained stimulation. PLCepsilon , on the other hand, predominantly accounts for sustained PI hydrolysis. Consistent with this observation, reconstitution of PLCepsilon in knockdown cells dose-dependently increases sustained, but not acute, agonist-stimulated PI hydrolysis. Furthermore, combined knockdown of both PLCepsilon and PLCbeta 3 additively inhibits PI hydrolysis, suggesting independent regulation of each isoform. Importantly, ubiquitination of inositol 1,4,5-trisphosphate (IP3) receptors correlates with sustained, but not acute, activation of PLCepsilon or PLCbeta 3. In conclusion, GPCR agonists ET 1, LPA and thrombin activate endogenous PLCepsilon and PLCbeta 3 in Rat-1 fibroblasts. Activation of these PLC isoforms displays agonist-specific temporal profiles; however, PLCbeta 3 is predominately involved in acute and PLCepsilon in sustained PI hydrolysis.


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