Exogenous nanomolar zinc ion (Zn) as a negative modulator of neuromuscular transmission via presynaptic mechanism in mouse diaphragm.

Zinc (Zn) is the second most abundant trace element after iron, with most of it is stored in skeletal muscles. Although a large part of Zn is tightly bound to metalloproteins, the small portion of free Zn can participate in nerve signaling. Here we examined the effects of Zn at nanomolar concentrations on neuromuscular transmission in the diaphragm, the main respiratory muscle. Zn reduced spontaneous neurotransmitter release at both lowered and physiological external Ca levels. Additionally, Zn effectively decreased the probability of neurotransmitter release upon single nerve stimulation under lowered external Ca, and inhibited Ca-independent sucrose-induced exocytosis. At physiological external Ca concentration, Zn decreased neurotransmitter release during low-frequency stimulation. The reduction became increased during short trains of moderate-to-high frequency stimuli. Furthermore, Zn diminished both neurotransmitter release and the participation of dye-labeled synaptic vesicles in exocytosis during prolonged nerve firing at moderate frequency. Zn aggravated muscle fatigue and impaired contraction recovery upon nerve stimulation. This was linked to a reduction in peak inspiratory flow in mice, an indicator of diaphragm function, after injection of low-dose Zn. Our data suggest that at nanomolar concentrations, Zn is a negative modulator of neuromuscular function.