Adenylyl cyclase type V deletion increases basal left ventricular function and reduces left ventricular contractile responsiveness to β-adrenergic stimulation

We tested the hypothesis that deletion of adenylyl cyclase type V (AC(V)) would be associated with decreased left ventricular (LV) contractile function and responsiveness to beta-adrenergic receptor (beta AR) stimulation. Absence of cardiac ACV expression was confirmed by RT-PCR and immunoblotting in ACV-deleted mice (AC(V)(-/-)). Compared to sibling mice with normal amounts of AC(V) ( CON), basal and water-soluble forskolin derivative NKH477-stimulated cAMP production was reduced in both LV homogenates and in isolated cardiac myocytes. Basal LV + dP/dt ( isolated perfused hearts) was increased ( CON: 3649 +/- 247 mmHg/s; AC(V)(-/-): 4625 +/- 350 mmHg/s; p = 0.035, n = 10), but the potency of dobutamine on LV + dP/dt was decreased by AC(V) deletion ( log EC50: CON: - 6.83 +/- 0.14 M; AC(V)(-/-): - 5.99 +/- 0.15 M; p = 0.0007, n = 10). The initial rates of ATP-dependent sarcoplasmic reticulum calcium uptake, assessed in LV homogenates, showed that ACV deletion increased SERCA2a af. nity for Ca2+ ( log EC50: CON: - 5.94 +/- 0.03 M; AC(V)(-/-): - 6.09 +/- 0.02 M; p = 0.001, n = 8). ACV deletion is also associated with increased phospholamban phosphorylation, decreased type 1 protein phosphatase catalytic subunit content and activity, and reduced cardiac G alpha s protein content. In conclusion, ACV deletion has a favorable effect on basal LV function despite reduced cAMP levels. Increased SERCA2a affinity for Ca2+ and increased phospholamban phosphorylation are contributing factors. However, ACV deletion is associated with reduced LV contractile responsiveness to beta AR stimulation, an effect that is associated with reduced G alpha s protein content and reduced cAMP generating capacity in cardiac myocytes.