INSERM U-637 Physiopathologie Cardiovasculaire, Montpellier, France

Ca²⁺ release from intracellular stores plays an important role in the regulation of muscle contraction and electrical signals that determine the heart rhythm. In the heart, Ca²⁺ released from sarcoplasmic reticulum (SR), is the principal determinant of cardiac contractility. SR Ca²⁺ release is controlled by dedicated molecular machinery, composed of the cardiac ryanodine receptor (RyR2). Several Ca²⁺ binding proteins, including calmodulin and calsequestrin, bind Zn²⁺ suggesting that Zn²⁺ can compete with Ca²⁺ and can modulate the structure and function of many proteins involved in cardiac EC-coupling. We demonstrated for the first time the variations in intracellular free Zn²⁺ level ([Zn²⁺]_i) and its important role in cardiac EC-coupling by using confocal microscopy in cardiomyocytes (loaded with a Zn²⁺-specific dye, FluoZin-3) isolated from normal and diabetic rats. In addition our data for the first time demonstrated that not only [Zn²⁺]_i played important role in the hyperphosphorylation of CaMKII, which is a key regulatory enzyme of RyR2, but also it induced activation of PKC and hyperphosphorylation of ERK-1 and NF-kB due to oxidized protein thiol level. Activation of ERK-1 induced the serine phosphorylation and participated diabetes-induced heart dysfunction via an inhibition in insulin-signaling pathway. Therefore, our data showed the important role of [Zn²⁺]_i in regulation of heart function as well as in alteration of transcription and gene expression. [Zn²⁺]_i is not only a secondary actor in EC-coupling but also it is a second messenger in cardiomyocytes which indicate its importance in the fine control of diseased heart.

(Supported by TUBITAK- SBAG-107S427and -SBAG-107S304, COST BM0602).