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- Title
Decreased L-Type Ca<sup>2+</sup> Current in Cardiac Myocytes of Type 1 Diabetic Akita Mice Due to Reduced Phosphatidylinositol 3-Kinase Signaling.
- Authors
Zhongju; Lu; Ya-Ping Jiang; Xin-Hua Xu; Ballou, Lisa M.; Cohen, Ira S.; Lin, Richard Z.
- Abstract
OBJECTIVE--Contraction of cardiac myocytes is initiated by Cap2+ 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 Ins2Akita 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 (ICa,L) density in myocytes compared with control nondiabetic littermates. The lower I[sub Ca,L] density in myocytes from diabetic mice is due at least in part to reduced cell surface expression of the LTCC. I[sub 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 ICa,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 ICa,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. Diabetes 56:2780-2789, 2007
- Publication
Diabetes, 2007, Vol 56, Issue 11, p2780
- ISSN
0012-1797
- Publication type
Academic Journal
- DOI
10.2337/db06-1629