OBJECTIVE—Contraction of cardiac myocytes is initiated by Ca²⁺ entry through the voltage-dependent l-type Ca²⁺ channel (LTCC). Previous studies have shown that phosphatidylinositol (PI) 3-kinase signaling modulates LTCC function. Because PI 3-kinases are key mediators of insulin action, we investigated whether LTCC function is affected in diabetic animals due to reduced PI 3-kinase signaling.

RESEARCH DESIGN AND METHODS—We used whole-cell patch clamping and biochemical assays to compare cardiac LTCC function and PI 3-kinase signaling in insulin-deficient diabetic mice heterozygous for the Ins2^Akita mutation versus nondiabetic littermates.

RESULTS—Diabetic mice had a cardiac contractility defect, reduced PI 3-kinase signaling in the heart, and decreased l-type Ca²⁺ current (I_Ca,L) density in myocytes compared with control nondiabetic littermates. The lower I_Ca,L density in myocytes from diabetic mice is due at least in part to reduced cell surface expression of the LTCC. I_Ca,L density in myocytes from diabetic mice was increased to control levels by insulin treatment or intracellular infusion of PI 3,4,5-trisphosphate [PI(3,4,5)P₃]. This stimulatory effect was blocked by taxol, suggesting that PI(3,4,5)P₃ stimulates microtubule-dependent trafficking of the LTCC to the cell surface. The voltage dependence of steady-state activation and inactivation of I_Ca,L was also shifted to more positive potentials in myocytes from diabetic versus nondiabetic animals. PI(3,4,5)P₃ infusion eliminated only the difference in voltage dependence of steady-state inactivation of I_Ca,L.

CONCLUSIONS—Decreased PI 3-kinase signaling in myocytes from type 1 diabetic mice leads to reduced Ca²⁺ entry through the LTCC, which might contribute to the negative effect of diabetes on cardiac contractility.