Enhanced cardiac function in transgenic mice expressing a Ca2+-stimulated adenylyl cyclase

The predominant functional adenylyl cyclases normally expressed in cardiac tissue and coupled to P-adrenergic receptors are inhibited by micromolar Ca2+ concentration. To modify the overall balance of activities, we have generated transgenic mice expressing the Ca2+-stimulatable adenylyl cyclase type 8 (AC8) specifically in the heart. AC activity is increased by at least 7-fold in heart membranes from transgenic animals and is stimulated by Ca2+ in the same range of concentration that inhibits the endogenous activity. Moreover, the in vivo basal protein kinase A activity was augmented 4-fold. Overexpression of AC8 in the heart has no detrimental consequences on global cardiac function. Basal heart rate and contractile function, measured by noninvasive echocardiography, were unchanged. In contrast, on release of parasympathetic tone, the intrinsic contractility is heightened and unresponsive to further beta-adrenergic receptor stimulation. AC8 transgenic mice thus represent an original model to investigate the relative influence of Ca2+ and cAMP on cardiac function within a phenotype of enhanced cardiac contractility and relaxation.