Multiple actions of zinc on transmitter release at mouse end-plates

Abstract

In mouse diaphragm, the increase in frequency of mini end-plate potentials (f _mepp), by Ca²⁺ or Ba²⁺ in 20 mM K⁺, was reversibly inhibited by Zn²⁺ in a manner consistent with competition between Zn²⁺ and Ca²⁺ at a site which interacts with only one atom of Zn with an apparent dissociation constant (K_i′) of about 0.015 mM. Between 0.5 mM and 2 mM, Zn²⁺ caused a rapid and reversible dose-dependent increasef _mepp in 20 mM K⁺/0 Ca²⁺. Prolonged or repeated exposure to Zn²⁺ produced a slow increase inf _mepp followed by a decline, which once started, was not modified by of Zn²⁺. The time course was prolonged in raised Mg²⁺, bekanamycin, or in 5 mM K⁺ solution, and graded with Zn²⁺ concentration, but total numbers of MEPPs induced by 0.1 mM, 1 mM or 4 mM Zn²⁺ were not significantly different. Whenf _mepp fell it became insensitive to Ca²⁺, Ba²⁺, La³⁺ (in 20 mM K⁺), ethanol and raised osmotic pressure. Before complete block of responses to Ca²⁺, the Ca²⁺/f_mepp dose/response curve in 20 mM K⁺ was shifted to the right. These results indicate that Zn²⁺ enters the terminal via voltage-gated Ca²⁺ channels that interact in a complex way with these ions and then acts (a) as a partial agonist at sites where Ca²⁺ normally governs transmitter release, and (b) to produce irreversible changes in the nerve terminal, associated with a rise and subsequent fall off _mepp and loss of sensitivity of the release mechanism to Ca²⁺ and other agents.