Transgenic replacement of type V adenylyl cyclase identifies a critical mechanism of β‐adrenergic receptor dysfunction in the Gαq overexpressing mouse

Publisher Website
Google Scholar
Abstract
Chronic activation of Gq coupled receptors, or overexpression of Gαq, 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 Gαq 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 Gαq transgenics resulting in animals (ACV/Gαq) that had restored levels of forskolin stimulated AC activities in cardiac membranes. In addition, basal cardiac AC activities were normalized in the ACV/Gαq mice (NTG=23±4.4, Gαq=14±3.6, ACV/Gαq=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 Gαq 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.

This publication has 15 references indexed in Scilit: