RRC ID 2047
Author Maruyama Y, Nishida M, Sugimoto Y, Tanabe S, Turner JH, Kozasa T, Wada T, Nagao T, Kurose H.
Title Galpha(12/13) mediates alpha(1)-adrenergic receptor-induced cardiac hypertrophy.
Journal Circ Res
Abstract 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.
Volume 91(10)
Pages 961-9
Published 2002-11-15
DOI 10.1161/01.res.0000043282.39776.7c
PMID 12433842
MeSH ADP Ribose Transferases / pharmacology Adaptor Proteins, Signal Transducing* Adenoviridae / genetics Animals Animals, Newborn Botulinum Toxins / pharmacology Cardiomegaly / etiology Cardiomegaly / metabolism* Carrier Proteins / biosynthesis Carrier Proteins / genetics Carrier Proteins / pharmacology Cells, Cultured DNA-Binding Proteins / genetics DNA-Binding Proteins / metabolism* Enzyme Activation / drug effects Enzyme Activation / physiology Enzyme Inhibitors / metabolism Enzyme Inhibitors / pharmacology GTP-Binding Protein alpha Subunits, G12-G13 GTP-Binding Protein alpha Subunits, Gq-G11 Heterotrimeric GTP-Binding Proteins / genetics Heterotrimeric GTP-Binding Proteins / metabolism* JNK Mitogen-Activated Protein Kinases Mitogen-Activated Protein Kinases / antagonists & inhibitors Mitogen-Activated Protein Kinases / metabolism Myocardium / cytology Myocardium / metabolism* Oxidants / pharmacology Peptide Fragments / biosynthesis Peptide Fragments / genetics Peptide Fragments / pharmacology Pertussis Toxin / pharmacology Protein Subunits / antagonists & inhibitors Protein Subunits / metabolism Rats Rats, Sprague-Dawley Receptors, Adrenergic, alpha-1 / metabolism* Signal Transduction / drug effects Transfection rhoA GTP-Binding Protein / antagonists & inhibitors rhoA GTP-Binding Protein / metabolism
IF 14.467
Times Cited 79
DNA material AxCALacZ (RDB1745)