Genetic ablation or pharmacological inhibition of PI3K p110alpha, but not p110beta, reduced L-type Ca2+ channel current and contractility in cardiac myocytes.
PI3K p110alpha specifically regulates L-type calcium channels and cardiac contractility, providing a mechanistic link between PI3K signaling and cardiac function.
BACKGROUND: Phosphoinositide 3-kinase (PI3K) p110alpha plays a key role in insulin action and tumorigenesis. Myocyte contraction is initiated by an inward Ca(2+) current (I(Ca,L)) through the voltage-dependent L-type Ca(2+) channel (LTCC). The aim of this study was to evaluate whether p110alpha also controls cardiac contractility by regulating the LTCC. METHODS AND RESULTS: Genetic ablation of p110alpha (also known as Pik3ca), but not p110beta (also known as Pik3cb), in cardiac myocytes of adult mice reduced I(Ca,L) and blocked insulin signaling in the heart. p110alpha-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 p110alpha decreased I(Ca,L) and contractility in canine myocytes. Inhibition of p110beta did not reduce I(Ca,L). CONCLUSIONS: PI3K p110alpha but not p110beta regulates the LTCC in cardiac myocytes. Decreased signaling to p110alpha reduces the number of LTCCs on the cell surface and thus attenuates I(Ca,L) and contractility.
Lu et al. (Tue,) conducted a other in Cardiac contractile dysfunction. Genetic ablation or pharmacological inhibition of PI3K p110alpha vs. p110beta ablation/inhibition or control was evaluated on L-type Ca(2+) channel (LTCC) current (I(Ca,L)) and contractility. Genetic ablation or pharmacological inhibition of PI3K p110alpha, but not p110beta, reduced L-type Ca2+ channel current and contractility in cardiac myocytes.