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J Biol Chem, Vol. 273, Issue 31, 19772-19777, July 31, 1998

Temporal Dispersion of Activation of Phospholipase C-1 and - Isoforms by Angiotensin II in Vascular Smooth Muscle Cells
ROLE OF _q/11, ₁₂, AND G PROTEIN SUBUNITS

From the Department of Medicine, Division of Cardiology, Emory University, Atlanta, Georgia 30322

Activation of phospholipase C (PLC) is one of the earliest events in angiotensin II (Ang II) type 1 (AT₁) receptor (R)-mediated signal transduction in vascular smooth muscle cells (VSMCs). The coupling mechanisms of AT₁ Rs to PLC, however, are controversial, because both tyrosine phosphorylation of PLC- and G protein-dependent PLC- activation pathways have been reported. The expression of PLC-1, furthermore, has not been consistently demonstrated in VSMCs. Here we identified the PLC subtypes and subunits of heterotrimeric G proteins involved in AT₁ R-PLC coupling using cultured rat VSMCs. Western analysis revealed the expression of PLC-1, -1, and -1 in VSMCs. Ang II-stimulated inositol trisphosphate (IP₃) formation measured at 15 s, which corresponds to the peak response, was significantly inhibited by electroporation of antibodies against PLC-1, but not by anti-PLC- and - antibodies. Electroporation of anti-G_q/11 and -G₁₂ antibodies also showed significant inhibition of the Ang II-induced IP₃ generation at 15 s, while anti-G_i and G₁₃ antibodies were ineffective. Furthermore, in VSMCs electroporated with anti-G antibody and cells stably transfected with the plasmid encoding the G-binding region of the carboxyl terminus of -adrenergic receptor kinase1, the peak Ang II-stimulated PLC activity (at 15 s) was significantly inhibited. The tyrosine kinase inhibitor, genistein, had no effect on the peak response to Ang II stimulation, but significantly inhibited IP₃ production after 30 s, a time period which temporally correlated with PLC- tyrosine phosphorylation in response to Ang II. Moreover, electropor-ation of anti-PLC- antibody markedly inhibited the IP₃ production measured at 30 s, indicating that tyrosine phosphorylation of PLC- contributes mainly to the later phase of PLC activation. Thus, these results suggest that: 1) AT₁ receptors sequentially couple to PLC-1 via a heterotrimeric G protein and to PLC- via a downstream tyrosine kinase; 2) the initial AT₁ receptor-PLC-1 coupling is mediated by G_q/11 and G₁₂; 3) G acts as a signal transducer for activation of PLC in VSMCs. The sequential coupling of AT₁ receptors to PLC-1 and PLC-, as well as dual coupling of AT₁ receptors to distinct G proteins, suggests a novel mechanism for a temporally controlled, highly organized and convergent Ang II-signaling network in VSMCs.

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