Gα 12/13 Mediates α 1 -Adrenergic Receptor–Induced Cardiac Hypertrophy

Abstract

In neonatal cardiomyocytes, activation of the G q -coupled α 1 -adrenergic receptor (α 1 AR) induces hypertrophy by activating mitogen-activated protein kinases, including c-Jun NH 2 -terminal kinase (JNK). Here, we show that JNK activation is essential for α 1 AR-induced hypertrophy, in that α 1 AR-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 α 1 AR-induced JNK activation and hypertrophic responses by generating several recombinant adenoviruses that express polypeptides capable of inhibiting the function of specific G-protein subunits. α 1 AR-induced JNK activation was inhibited by the expression of carboxyl terminal regions of Gα q , Gα 12 , and Gα 13 . 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. α 1 AR-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 Gα 12 and Gα 13 but not by Gα q . Our findings suggest that α 1 AR-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.