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 β-adrenergic receptor (βAR) stimulation. Absence of cardiac AC_V expression was confirmed by RT-PCR and immunoblotting in AC_V-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 AC_V deletion increased SERCA2a affinity for Ca²⁺ (log EC₅₀: CON: -5.94 ± 0.03 M; AC_V^-/-:-6.09 ± 0.02 M; p = 0.001, n = 8). AC_V deletion is also associated with increased phospholamban phosphorylation, decreased type 1 protein phosphatase catalytic subunit content and activity, and reduced cardiac Gαs protein content. In conclusion, AC_V 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, AC_V deletion is associated with reduced LV contractile responsiveness to βAR stimulation, an effect that is associated with reduced Gαs protein content and reduced cAMP generating capacity in cardiac myocytes.