Micromolar concentrations of Zn depress cellular excitability through a blockade of calcium current in rat adrenal slices.

The present work, using chromaffin cells in rat adrenal slices (RCCs), aims to describe what type of ionic current alterations induced by zinc underlies their effects reported on synaptic transmission. Thus, Zn blocked calcium channels of RCCs in a time- and concentration-dependent manner with an IC of 391 μM. This blockade was partially reversed upon washout and was greater at more depolarizing holding potentials (i.e. 32 ± 5% at -110 mV, and 43 ± 6% at -50 mV, after 5 min perfusion). In ω-toxins-sensitive calcium channels (N-, P- and Q-types), Zncaused a lower blockade of I, 33.3%, than in ω-toxins-resistant ones (L-type, 55.3%; and R-type, 90%). This compound inhibited calcium current at all test potentials and shows a shift of the I-V curve to more depolarized values of about 10 mV. The sodium current was not blocked by acute application of high Znconcentrations. Voltage-dependent potassium current was marginally affected by high Zn concentrations showing no concentration-dependence. Nevertheless, calcium- and voltage-dependent potassium current was drastically depressed in a dose-dependent manner, with an IC of 453 μM. This blockade was related to the prevention of Ca influx through voltage-dependent calcium channels coupled to BK channels. Under current-clamp conditions, RCCs exhibit a resting potential of -50.7 mV, firing spontaneous APs (1-2 spikes/s) generated by the opening of Na and Ca-channels, and terminated by the activation of voltage and Ca-activated K-channels (BK). We found that the blockade of these ionic currents by Zn led to a drastic alteration of cellular excitability with a depolarization of the membrane potential, the slowdown and broadening of the APs and the severe reduction of the after hyperpolarization (AHP) which led to a decrease in the APs firing frequency. Taken together, these results point to a neurotoxic action evoked by zinc that is associated with changes to cellular excitability by blocking the ionic currents responsible for both the neurotransmitter release and the action potentials firing.