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

  1. Zhongju Lu1,
  2. Ya-Ping Jiang2,
  3. Xin-Hua Xu3,
  4. Lisa M. Ballou2,
  5. Ira S. Cohen1 and
  6. Richard Z. Lin1,2,4
  1. 1Department of Physiology and Biophysics and the Institute of Molecular Cardiology, Stony Brook University, Stony Brook, New York
  2. 2Department of Medicine, Stony Brook University, Stony Brook, New York
  3. 3Department of Cardiac Surgery, 2nd Hospital Xiang Ya Medical School, Central South University, Changsha, China
  4. 4Department of Veterans Affairs Medical Center, Northport, New York
  1. 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

Abstract

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 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 ICa,L density in myocytes from diabetic mice is due at least in part to reduced cell surface expression of the LTCC. ICa,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.

Footnotes

  • Published ahead of print at http://diabetes.diabetesjournals.org on 31 July 2007. DOI: 10.2337/db06-1629.

    The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Received November 21, 2006.
    • Accepted July 26, 2007.
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  1. Diabetes vol. 56 no. 11 2780-2789
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