title: Signal transduction in atria and ventricles of mice with transient cardiac expression of activated G protein alpha(q).
abstract: We recently showed that the transient expression of a hemagglutinin (HA) epitope-tagged, constitutively active mutant of the G protein alpha(q) subunit (HAalpha(q)*) in the hearts of transgenic mice is sufficient to induce cardiac hypertrophy and dilatation that continue to progress after HAalpha(q)* protein becomes undetectable. We demonstrated that the activity of phospholipase Cbeta, the immediate downstream target of activated Galpha(q), is increased at 2 weeks, when HAalpha(q)* is expressed, but also at 10 weeks, when HAalpha(q)* is no longer detectable. This observation suggested that the transient HAalpha(q)* expression causes multiple, persistent changes in cellular signaling pathways. We now demonstrate changes in the level, activity, or both of several signaling components, including changes in the amount and hormone responsiveness of phospholipase Cbeta enzymes, in the basal level of diacylglycerol (which predominantly reflects activation of phospholipase D), in the amount or distribution of protein kinase C (PKC) isoforms (PKCalpha, PKCdelta, and PKCepsilon), and in the amount of several endogenous G proteins. These changes vary depending on the isoform of the signaling molecule, the chamber in which it is expressed, and the presence or absence of HAalpha(q)*. Our results suggest that a network of linked signaling functions determines the development of hypertrophy. They also suggest that atria and ventricles represent different signaling domains. It is likely that such changes occur in other model systems in which the activity of a single signaling component is increased, either due to an activating mutation or due to overexpression of the wild type.
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. mende@calvin.bwh.harvard.edu
authors.forename: U
authors.initials: U
authors.lastname: Mende
authors.forename: A
authors.initials: A
authors.lastname: Kagen
authors.forename: M
authors.initials: M
authors.lastname: Meister
authors.forename: E J
authors.initials: EJ
authors.lastname: Neer
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000201:enzymology* / Q000235:genetics; D002311:Cardiomyopathy, Dilated / Q000201:enzymology* / Q000235:genetics; D004075:Diglycerides / Q000378:metabolism; D004789:Enzyme Activation; D019204:GTP-Binding Proteins / Q000378:metabolism*; D015870:Gene Expression; D006325:Heart Atria; D006352:Heart Ventricles; D007295:Inositol Phosphates / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000378:metabolism*; D009206:Myocardium / Q000201:enzymology*; D018995:Myosin Heavy Chains / Q000235:genetics; D009928:Organ Specificity; D010740:Phospholipases / Q000378:metabolism; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D004075:Diglycerides; D007295:Inositol Phosphates; D009124:Muscle Proteins; D020033:Protein Isoforms; D011993:Recombinant Fusion Proteins; D011493:Protein Kinase C; D010740:Phospholipases; D019204:GTP-Binding Proteins; D018995:Myosin Heavy Chains