Insulin-like growth factor-1 and PTEN deletion enhance cardiac L-type Ca2+ currents via increased PI3Kα/PKB signaling

Ca2+ influx through the L-type Ca2+ channel (I-Ca,I-L) is a key determinant of cardiac contractility and is modulated by multiple signaling pathways. Because the regulation of ICa, L by phosphoinositide-3-kinases (PI3Ks) and phospho-inositide-3-phosphatase ( PTEN) is unknown, despite their involvement in the regulation of myocardial growth and contractility, I-Ca,I-L was recorded in myocytes isolated from mice overexpressing a dominant-negative p110 alpha mutant (DN-p110 alpha) in the heart, lacking the PI3K gamma gene (PI3K gamma(-/-)) 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,I- L densities were larger (P < 0.01) in PTEN-/- myocytes compared with littermate controls, PI3K gamma(-/-), or DN-p110 alpha myocytes and showed negative shifts in voltage dependence of current activation. The I-Ca,I-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-p110 alpha double mutant mice but not in PTEN-/-/PI3K gamma(-/-) mice. On the other hand, application of insulin-like growth factor-1 (IGF-1), an activator of PKB, increased I-Ca,I-L in control and PI3K gamma(-/-), while having no effects on I-Ca,I-L in DN-p110 alpha or PTEN-/- mice. The I-Ca,I-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,I-L via PI3K alpha-dependent increase in PKB activation.