Transgenic replacement of type V adenylyl cyclase identifies a critical mechanism of beta-adrenergic receptor dysfunction in the G(alpha q) overexpressing mouse

Chronic activation of G(q) 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 ad enylyl 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 o bserved similar to 45% decrease in type V AC expression and function compar ed to non-transgenic (NTG) is the basis of the above phenotype, Transgenic mice mere generated that overexpressed by similar to 50% the rat type V AC in the heart using the a-myosin heavy chain promoter, These mice were mated with the G(alpha q) transgenics resulting in animals (ACV/G(alpha g)) that had restored levels of forskolin stimulated AC activities in cardiac membr anes. In addition, basal cardiac AC activities mere 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 activitie s (59 +/- 8.9, 34 +/- 4.6, 52 +/- 6.7 pmol/min/mg respectively). Cardiac co ntractility was also improved by ACV replacement, with increased fractional shortening (51 +/- 2%, 36 +/- 6%, 46 +/- 3% respectively). In contrast, hy pertrophy and expression of hypertrophy associated fetal genes mere not aff ected. Thus the observed decrease in type V AC that accompanies the develop ment of the cardiac phenotype in the G(alpha q) model is the dominant mecha nism of dysfunctional beta AR signalling and contractility. In contrast, th e decrease in type V AC or beta AR signalling to cAMP is not the basis of t he hypertrophic response. (C) 1999 Federation of European Biochemical Socie ties.