Zinc-induced changes in ionic currents of clonal rat pancreatic β-cells:: activation of ATP-sensitive K+ channels

1.The effects of zinc (Zn2+) on excitability and ionic conductances were analysed on RINm5F insulinoma cells under whole-cell and outside-out patch-clamp recording conditions. 2.We found that extracellular application of 10-20 muM Zn2+ induced a reversible abolition of Ca2+ action potential firing, which was accompanied by an hyperpolarisation of the resting membrane potential. 3. Higher concentrations of Zn2+, in the tens to hundreds micromolar range, induced a reversible reduction of voltage-gated Ca2+ and, to a lesser extent, K+ currents. Low-voltage-activated,ed Ca2+ currents were more sensitive to Zn2+ block than high voltage-activated Ca2+ currents. 4. The Zn2+-induced hyperpolarisation arose from a dose-dependent increase in a voltage-independent K+ conductance that was pharmacologically identified as an ATP-sensitive K+ (K-ATP) conductance. The effect was rapid in onset, readily reversible, voltage independent, and related to intracellular ATP concentration. In the presence of 1 mM intracellular ATP, half-maximal activation of K-ATP channels was obtained with extracellular application of 1.7 muM Zn2+ 5. Single channel analysis revealed that extracellular Zn2+ increased the K-ATP channel open state probability with no change in the single channel conductance. 6. Our data support the hypothesis that Zn2+ binding to K-ATP protein subunits results in an activation of the channels, therefore regulating the resting membrane potential and decreasing the excitability of RINm5F cells. Taken together, our results suggest that Zn2+ can influence insulin secretion in pancreatic beta -cells through a negative feedback loop, involving both K-ATP and voltage-gated conductances.