Zinc modulation of basal and β-adrenergically stimulated L-type Ca²⁺ current in rat ventricular cardiomyocytes: consequences in cardiac diseases

Abstract

Zinc exists in biological systems as bound and histochemically reactive free Zn²⁺ in the nanomolar range. Zinc is required as either structural or catalytic component for a large number of enzymes. It also modulates current passage through many ion channels. Here, we reinvestigated the effects of extracellular and intracellular Zn²⁺ on the L-type Ca²⁺ current (I _CaL) and its modulation by β-adrenergic stimulation in rat ventricular cardiomyocytes. In the absence of Ca²⁺ ions, Zn²⁺ could permeate through the L-type channel at much lower concentrations and at a more positive voltage range, but with a lower permeability than Ca²⁺. In the presence of Ca²⁺, extracellular Zn²⁺ demonstrated strong bimodal inhibitory effects on the I _CaL, with half-inhibition occurring around 30 nM, i.e., in the range of concentrations found in the plasma. Intracellular Zn²⁺ also significantly inhibited the I _CaL with a half-inhibitory effect at 12.7 nM. Moreover, β-adrenergic stimulation was markedly reduced by intracellular Zn²⁺ at even lower concentrations (<1 nM) as a consequence of Zn²⁺-induced inhibition of the adenylyl cyclase. All these effects appeared independent of redox variations and were not affected by dithiothreitol. Thus, both basal intracellular and extracellular Zn²⁺ modulate transmembrane Ca²⁺ movements and their regulation by β-adrenergic stimulation. Considering that, in many pathological situations, including diabetes, the extracellular Zn²⁺ concentration is reduced and the intracellular one is increased, our results help to explain both Ca²⁺ overload and marked reduction in the β-adrenergic stimulation in these diseases.