Restoration of Defective L-type Ca2+ Current in Cardiac Myocytes of Type 2 Diabetic db/db Mice by Akt and PKC-ι

Diabetes is associated with an increased risk of heart failure and the development of a cardiomyopathy whose etiology is only partially understood. Ca2+ entry through the voltage-dependent L-type Ca2+ channel Ca(V)1.2 initiates the contractile cycle in cardiac myocytes. Decreased cardiac contractility and depressed Ca(V)1.2 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 Ca(V)1.2 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 Ca2+ current (I-Ca,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 I-Ca,I-L. Akt1 and Akt2 were as effective as PIP3 in restoring the I-Ca,I-L density in db/db myocytes but did not affect the voltage dependence of current activation. The infusion of atypical PKC-iota (the human homolog of mouse PKC-lambda) caused a small but significant increase in the I-Ca,I-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-lambda signaling is mainly responsible for the depressed Ca(V)1.2 function in the hearts of db/db mice with type 2 diabetes.