Insulin-like growth factor-1 and PTEN deletion enhance cardiac L-type Ca2+ currents via increased PI3Kalpha/PKB signaling.

Ca2+ influx through the L-type Ca2+ channel (I(Ca,L)) is a key determinant of cardiac contractility and is modulated by multiple signaling pathways. Because the regulation of I(Ca,L) by phosphoinositide-3-kinases (PI3Ks) and phosphoinositide-3-phosphatase (PTEN) is unknown, despite their involvement in the regulation of myocardial growth and contractility, I(Ca,L) was recorded in myocytes isolated from mice overexpressing a dominant-negative p110alpha mutant (DN-p110alpha) in the heart, lacking the PI3Kgamma gene (PI3Kgamma(-/-)) or with muscle-specific ablation of PTEN (PTEN(-/-)). Combinations of these genetically altered mice were also examined. Although there were no differences in the expression level of CaV1.2 proteins, basal I(Ca,L) densities were larger (P<0.01) in PTEN(-/-) myocytes compared with littermate controls, PI3Kgamma(-/-), or DN-p110alpha myocytes and showed negative shifts in voltage dependence of current activation. The I(Ca,L) differences seen in PTEN(-/-) mice were eliminated by pharmacological inhibition of either PI3Ks or protein kinase B (PKB) as well as in PTEN(-/-)/DN-p110alpha double mutant mice but not in PTEN(-/-)/PI3Kgamma(-/-) mice. On the other hand, application of insulin-like growth factor-1 (IGF-1), an activator of PKB, increased I(Ca,L) in control and PI3Kgamma(-/-), while having no effects on I(Ca,L) in DN-p110alpha or PTEN(-/-) mice. The I(Ca,L) increases induced by IGF-1 were abolished by PKB inhibition. Our results demonstrate that IGF-1 treatment or inactivation of PTEN enhances I(Ca,L) via PI3Kalpha-dependent increase in PKB activation.