title: Transgenic replacement of type V adenylyl cyclase identifies a critical mechanism of beta-adrenergic receptor dysfunction in the G alpha q overexpressing mouse.
abstract: Chronic activation of Gq coupled receptors, or overexpression of G alpha q, in cardiomyocytes results in hypertrophy, enhanced expression of fetal genes, decreased basal and beta-adrenergic receptor (beta AR) stimulated adenylyl cyclase (AC) activities, and depressed cardiac contractility in vivo. Among several abnormalities of the beta AR-Gs-AC pathway that occur in G alpha q overexpressing transgenic mice, we have investigated whether the observed approximately 45% decrease in type V AC expression and function compared to non-transgenic (NTG) is the basis of the above phenotype. Transgenic mice were generated that overexpressed by approximately 50% the rat type V AC in the heart using the alpha-myosin heavy chain promoter. These mice were mated with the G alpha q transgenics resulting in animals (ACV/G alpha q) that had restored levels of forskolin stimulated AC activities in cardiac membranes. In addition, basal cardiac AC activities were normalized in the ACV/G alpha q mice (NTG=23+/-4.4, G alpha q=14+/-3.6, ACV/G alpha q=29+/-5.3 pmol/min/mg) as were maximal isoproterenol stimulated activities (59+/-8.9, 34+/-4.6, 52+/-6.7 pmol/min/mg respectively). Cardiac contractility was also improved by ACV replacement, with increased fractional shortening (51+/-2%, 36+/-6%, 46+/-3% respectively). In contrast, hypertrophy and expression of hypertrophy associated fetal genes were not affected. Thus the observed decrease in type V AC that accompanies the development of the cardiac phenotype in the G alpha q model is the dominant mechanism of dysfunctional beta AR signalling and contractility. In contrast, the decrease in type V AC or beta AR signalling to cAMP is not the basis of the hypertrophic response.
authors.affiliation: Department of Pharmacology, University of Cincinnati College of Medicine, OH 45267, USA.
authors.forename: N M
authors.initials: NM
authors.lastname: Tepe
authors.forename: S B
authors.initials: SB
authors.lastname: Liggett
mesh_terms: D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D006332:Cardiomegaly / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D002384:Catalysis; D004195:Disease Models, Animal; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D019204:GTP-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics; D016276:Ventricular Function / Q000235:genetics
chemical_list: D000067956:Adenylyl Cyclase Inhibitors; D011943:Receptors, Adrenergic, beta; D019204:GTP-Binding Proteins; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D000262:Adenylyl Cyclases