12/13- and Rho-dependent activation of phospholipase C-ε by lysophosphatidic acid and thrombin receptors

Melinda D. Hains, Michele R. Wing, Savitri Maddileti, David P. Siderovski, T. Kendall Harden

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57 Scopus citations


Because phospholipase C ε (PLC-ε) is activated by Gα12/13 and Rho family GTPases, we investigated whether these G proteins contribute to the increased inositol lipid hydrolysis observed in COS-7 cells after activation of certain G protein-coupled receptors. Stimulation of inositol lipid hydrolysis by endogenous lysophosphatidic acid (LPA) or thrombin receptors was markedly enhanced by the expression of PLC-ε. Expression of the LPA1 or PAR1 receptor increased inositol phosphate production in response to LPA or SFLLRN, respectively, and these agonist-stimulated responses were markedly enhanced by coexpression of PLC-ε. Both LPA1 and PAR1 receptor-mediated activation of PLC-ε was inhibited by coexpression of the regulator of G protein signaling (RGS) domain of p115RhoGEF, a GTPase-activating protein for Gα12/13 but not by expression of the RGS domain of GRK2, which inhibits Gαq signaling. In contrast, activation of the G q-coupled M1 muscarinic or P2Y2 purinergic receptor was neither enhanced by coexpression with PLC-ε nor inhibited by the RGS domain of p115RhoGEF but was blocked by expression of the RGS domain of GRK2. Expression of the Rho inhibitor C3 botulinum toxin did not affect LPA- or SFLLRN-stimulated inositol lipid hydrolysis in the absence of PLC-ε but completely prevented the PLC-ε-dependent increase in inositol phosphate accumulation. Likewise, C3 toxin blocked the PLC-ε-dependent stimulatory effects of the LPA1, LPA2, LPA3, or PAR1 receptor but had no effect on the agonist-promoted inositol phosphate response of the M1 or P2Y2 receptor. Moreover, PLC-ε-dependent stimulation of inositol phosphate accumulation by activation of the epidermal growth factor receptor, which involves Ras- but not Rho-mediated activation of the phospholipase, was unaffected by C3 toxin. These studies illustrate that specific LPA and thrombin receptors promote inositol lipid signaling via activation of Gα12/13 and Rho.

Original languageEnglish
Pages (from-to)2068-2075
Number of pages8
JournalMolecular Pharmacology
Issue number6
StatePublished - 2006


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