Transgenic replacement of type V adenylyl cyclase identifies a critical mechanism of β-adrenergic receptor dysfunction in the G αq overexpressing mouse

Chronic activation of G q coupled receptors, or overexpression of G αq, in cardiomyocytes results in hypertrophy, enhanced expression of fetal genes, decreased basal and β-adrenergic receptor (βAR) stimulated adenylyl cyclase (AC) activities, and depressed cardiac contractility in vivo. Among several abnormalities of the βAR-Gs-AC pathway that occur in G αq overexpressing transgenic mice, we have investigated whether the observed ∼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 ∼50% the rat type V AC in the heart using the α-myosin heavy chain promoter. These mice were mated with the G αq transgenics resulting in animals (ACV/G αq) that had restored levels of forskolin stimulated AC activities in cardiac membranes. In addition, basal cardiac AC activities were normalized in the ACV/G αq mice (NTG=23±4.4, G αq=14±3.6, ACV/G αq=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 αq model is the dominant mechanism of dysfunctional βAR signalling and contractility. In contrast, the decrease in type V AC or βAR signalling to cAMP is not the basis of the hypertrophic response.