Background/aims: In myocytes from diabetic hearts, the reduction in the amplitude of the transient outward potassium current (I(to)) and the acceleration of its inactivation contribute to the action potential duration lengthening. Whereas the reduced amplitude is attributable to a reduced support of trophic factors, the mechanism underlying the acceleration of inactivation remains unknown. Ca(2+)/Calmodulin-dependent protein kinase II (CaMKII) modifies the inactivation kinetics of I(to). In this work we explored the role of CaMKII in the acceleration of I(to) current inactivation observed in diabetic myocytes.
Methods: We used patch-clamp and immunoblotting techniques in enzymatically-isolated myocytes from healthy and streptozotocin-induced diabetic rat hearts, and in blood samples from diabetic patients.
Results: In control myocytes, inhibition of either calmodulin or CaMKII accelerated I(to) current inactivation. However, in diabetic myocytes I(to) inactivation was already accelerated, and did not respond to calmodulin or CaMKII inhibition. Calmodulin protein abundance was significantly reduced in diabetic myocytes. Incubation of diabetic myocytes with insulin recovered calmodulin expression to normal values. A similar pattern of calmodulin expression appears in the blood of diabetic patients. Insulin treatment also restored I(to) current inactivation kinetics as well as the responsiveness to regulation by calmodulin.
Conclusion: Diabetes-induced acceleration of I(to) current inactivation is due to a reduced effect of CaMKII on I(to) channels as a result of a diabetes-induced reduction in calmodulin protein expression. A correct follow up of the insulin treatment could prevent this alteration.
Copyright 2008 S. Karger AG, Basel.