Insulin-Like Growth Factor-1 and PTEN Deletion Enhance Cardiac L-Type Ca2+ Currents via Increased PI3Kα/PKB Signaling

Ca 2+ influx through the L-type Ca 2+ 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 p110α mutant ( DN-p110α ) in the heart, lacking the PI3Kγ gene ( PI3Kγ −/− ) 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 Ca V 1.2 proteins, basal I Ca,L densities were larger ( P PTEN −/− myocytes compared with littermate controls, PI3Kγ −/− , or DN-p110α 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-p110α double mutant mice but not in PTEN −/− / PI3Kγ −/− 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 PI3Kγ −/− , while having no effects on I Ca,L in DN-p110α 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 PI3Kα-dependent increase in PKB activation.