Galpha(12/13) mediates alpha(1)-adrenergic receptor-induced cardiac hypertrophy.

Maruyama Y, Nishida M, Sugimoto Y, Tanabe S, Turner JH, Kozasa T, Wada T, Nagao T, Kurose H
Circ Res. 2002 91 (10): 961-9

PMID: 12433842 · DOI:10.1161/01.res.0000043282.39776.7c

In neonatal cardiomyocytes, activation of the G(q)-coupled alpha(1)-adrenergic receptor (alpha(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 alpha(1)AR-induced hypertrophy, in that alpha(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 alpha(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. alpha(1)AR-induced JNK activation was inhibited by the expression of carboxyl terminal regions of Galpha(q), Galpha(12), and Galpha(13). JNK activation was also inhibited by the Galpha(q/11)- or Galpha(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 Gbetagamma. alpha(1)AR-induced hypertrophic responses were inhibited by Galpha(q/11)- and Galpha(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 Galpha(12) and Galpha(13) but not by Galpha(q). Our findings suggest that alpha(1)AR-induced hypertrophic responses are mediated in part by a Galpha(12/13)-Rho-JNK pathway, in part by a G(q/11)-JNK pathway that is Rho independent, and in part by a Gbetagamma pathway that is JNK independent.

MeSH Terms (28)

Adaptor Proteins, Signal Transducing Adenoviridae ADP Ribose Transferases Animals Animals, Newborn Botulinum Toxins Cardiomegaly Carrier Proteins Cells, Cultured DNA-Binding Proteins Enzyme Activation Enzyme Inhibitors GTP-Binding Protein alpha Subunits, G12-G13 GTP-Binding Protein alpha Subunits, Gq-G11 Heterotrimeric GTP-Binding Proteins JNK Mitogen-Activated Protein Kinases Mitogen-Activated Protein Kinases Myocardium Oxidants Peptide Fragments Pertussis Toxin Protein Subunits Rats Rats, Sprague-Dawley Receptors, Adrenergic, alpha-1 rhoA GTP-Binding Protein Signal Transduction Transfection

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