Type 5 Adenylyl Cyclase Disruption Alters Not Only Sympathetic But Also Parasympathetic and Calcium-Mediated Cardiac Regulation

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Abstract
In a genetically engineered mouse line with disruption of type 5 adenylyl cyclase (AC5−/−), a major cardiac isoform, there was no compensatory increase in other isoforms of AC in the heart. Both basal and isoproterenol (ISO)-stimulated AC activities were decreased by 30% to 40% in cardiac membranes. The reduced AC activity did not affect cardiac function (left ventricular ejection fraction [LVEF]) at baseline. However, increases in LVEF after ISO were significantly attenuated in AC5−/− (PAC5−/− mice had a higher heart rate compared with wild-type (WT) mice (613±8 versus 523±11 bpm, PAC5−/−. In addition, baroreflex-mediated, ie, neuronally regulated, bradycardia after phenylephrine was also attenuated in AC5−/−. The carbachol-activated outward potassium current (at −40 mV) normalized to cell capacitance in AC5−/− (2.6±0.4 pA/pF, n=16) was similar to WT (2.9±0.3 pA/pF, n=27), but calcium (Ca2+)-mediated inhibition of AC activity and Ca2+ channel function were diminished in AC5−/−. Thus, AC5−/− attenuates sympathetic responsiveness and also impairs parasympathetic and Ca2+-mediated regulation of the heart, indicating that those actions are not only regulated at the level of the receptor and G-protein but also at the level of type 5 AC.