title: Restoration of defective L-type Ca2+ current in cardiac myocytes of type 2 diabetic db/db mice by Akt and PKC-ι.
abstract: Diabetes is associated with an increased risk of heart failure and the development of a cardiomyopathy whose etiology is only partially understood. Ca entry through the voltage-dependent L-type Ca channel CaV1.2 initiates the contractile cycle in cardiac myocytes. Decreased cardiac contractility and depressed CaV1.2 function have been reported in obese type 2 diabetic db/db mice. Here, we demonstrate that a reduction in phosphoinositide 3-kinase (PI3K) signaling is a major contributor to the altered function of CaV1.2 in db/db cardiac myocytes. Using the whole-cell patch clamp technique, we determined that intracellular infusion of cardiac myocytes from db/db mice with phosphatidylinositol 3,4,5-trisphosphate (PIP3), the second messenger produced by PI3K, increased the L-type Ca current (ICa,L) density nearly to the level seen in wild-type cells. PIP3 also reversed the positive shift in the voltage dependence of the steady-state current activation observed in db/db myocytes. Infusion of protein kinases that act downstream of PI3K also affected ICa,L. Akt1 and Akt2 were as effective as PIP3 in restoring the ICa,L density in db/db myocytes but did not affect the voltage dependence of current activation. The infusion of atypical PKC-ι (the human homolog of mouse PKC-λ) caused a small but significant increase in the ICa,L density and completely reversed the shift in voltage dependence of steady-state current activation. These results indicate that a defect in PI3K/PIP3/Akt/PKC-λ signaling is mainly responsible for the depressed CaV1.2 function in the hearts of db/db mice with type 2 diabetes.
authors.affiliation: Department of Physiology and Biophysics and the Institute of Molecular Cardiology, Stony Brook University, Stony Brook, NY, USA. zlu@notes.cc.sunysb.edu.
authors.forename: Zhongju
authors.initials: Z
authors.lastname: Lu
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Ballou
authors.forename: Ya-Ping
authors.initials: YP
authors.lastname: Jiang
authors.forename: Ira S
authors.initials: IS
authors.lastname: Cohen
authors.forename: Richard Z
authors.initials: RZ
authors.lastname: Lin
mesh_terms: D000818:Animals; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000378:metabolism; D018408:Patch-Clamp Techniques; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D000099293:Protein Kinase C-lambda
chemical_list: D020746:Calcium Channels, L-Type; D007527:Isoenzymes; D018129:Phosphatidylinositol Phosphates; D011493:Protein Kinase C; D051057:Proto-Oncogene Proteins c-akt; D000099293:Protein Kinase C-lambda; C514350:CACNA1C protein, mouse; C060974:phosphatidylinositol 3,4,5-triphosphate