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Decreased L-Type Ca²⁺ Current in Cardiac Myocytes of Type 1 Diabetic Akita Mice Due to Reduced Phosphatidylinositol 3-Kinase Signaling

¹ Department of Physiology and Biophysics and the Institute of Molecular Cardiology, Stony Brook University, Stony Brook, New York
² Department of Medicine, Stony Brook University, Stony Brook, New York
³ Department of Cardiac Surgery, 2nd Hospital Xiang Ya Medical School, Central South University, Changsha, China
⁴ Department of Veterans Affairs Medical Center, Northport, New York

Address correspondence and reprint requests to Richard Z. Lin, Department of Medicine, Division of Hematology and Oncology, Stony Brook University, Stony Brook, NY 11794-8151. E-mail: richard.lin{at}sunysb.edu

Abbreviations: I_Ca,L, L-type Ca²⁺ current; I-V, current density–voltage; LTCC, L-type Ca²⁺ channel; LVEDD, left ventricular end-diastolic diameter; LVESD, left ventricular end-systolic diameter; PI, phosphatidylinositol; PI(3,4,5)P₃, PI 3,4,5-trisphosphate; PI(4,5)P₂, PI 4,5-bisphosphate; V_1/2, membrane potential at which 50% of the channels are inactivated; V_h, membrane potential at which 50% of the channels are activated

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.

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