Loss of cardiac phosphoinositide 3-kinase p110α results in contractile dysfunction

BACKGROUND - Phosphoinositide 3-kinase (PI3K) p110α plays a key role in insulin action and tumorigenesis. Myocyte contraction is initiated by an inward Ca current (ICa,L) through the voltage-dependent L-type Ca channel (LTCC). The aim of this study was to evaluate whether p110α also controls cardiac contractility by regulating the LTCC. METHODS AND RESULTS - Genetic ablation of p110α (also known as Pik3ca), but not p110β (also known as Pik3cb), in cardiac myocytes of adult mice reduced ICa,L and blocked insulin signaling in the heart. p110α-null myocytes had a reduced number of LTCCs on the cell surface and a contractile defect that decreased cardiac function in vivo. Similarly, pharmacological inhibition of p110α decreased ICa,L and contractility in canine myocytes. Inhibition of p110β did not reduce ICa,L. CONCLUSIONS - PI3K p110α but not p110β regulates the LTCC in cardiac myocytes. Decreased signaling to p110α reduces the number of LTCCs on the cell surface and thus attenuates ICa,L and contractility.