Gα12/13Mediates α1-Adrenergic Receptor–Induced Cardiac Hypertrophy

Abstract

In neonatal cardiomyocytes, activation of the G_q-coupled α₁-adrenergic receptor (α₁AR) induces hypertrophy by activating mitogen-activated protein kinases, including c-Jun NH₂-terminal kinase (JNK). Here, we show that JNK activation is essential for α₁AR-induced hypertrophy, in that α₁AR-induced hypertrophic responses, such as reorganization of the actin cytoskeleton and increased protein synthesis, could be blocked by expressing the JNK-binding domain of JNK-interacting protein-1, a specific inhibitor of JNK. We also identified the classes and subunits of G proteins that mediate α₁AR-induced JNK activation and hypertrophic responses by generating several recombinant adenoviruses that express polypeptides capable of inhibiting the function of specific G-protein subunits. α₁AR-induced JNK activation was inhibited by the expression of carboxyl terminal regions of Gα_q, Gα₁₂, and Gα₁₃. JNK activation was also inhibited by the Gα_q/11- or Gα_12/13-specific regulator of G-protein signaling (RGS) domains and by C3 toxin but was not affected by treatment with pertussis toxin or by expression of the carboxyl terminal region of G protein–coupled receptor kinase 2, a polypeptide that sequesters Gβγ. α₁AR-induced hypertrophic responses were inhibited by Gα_q/11- and Gα_12/13-specific RGS domains, C3 toxin, and the carboxyl terminal region of G protein–coupled receptor kinase 2 but not by pertussis toxin. Activation of Rho was inhibited by carboxyl terminal regions of Gα₁₂ and Gα₁₃ but not by Gα_q. Our findings suggest that α₁AR-induced hypertrophic responses are mediated in part by a Gα_12/13-Rho-JNK pathway, in part by a G_q/11-JNK pathway that is Rho independent, and in part by a Gβγ pathway that is JNK independent.