Zn2+ stimulates spontaneous transmitter release at mouse neuromuscular junctions

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Abstract
1 Experiments were carried out to examine the effect of Zn2+ on the rate of spontaneous release of transmitter at the neuromuscular junction of the mouse diaphragm muscle, in the presence and absence of external Ca2+. Miniature endplate potentials (m.e.p.ps) were measured in vitro. 2 Zn2+ markedly elevated the frequency of m.e.p.ps without affecting the resting membrane potential of muscle fibres. This effect was time- and concentration-dependent but was independent of the presence of external Ca2+. In a Ca2+-free bathing solution, Zn2+ frequently produced twitching in several fibres. The twitching dislodged the microelectrode. Replacement of the 10 mm NaCl in the Ca2+-free solution with equimolar KCl overcame this difficulty. The experiments summarized below were done in the Ca2+-free bathing solution which contained 10 mm KCl instead of 10 mm NaCl. 3 The effect of Zn2+ was transient and required a latent period of many minutes. Low temperature (24°C) increased the length of this latent period and reduced the maximum effect of Zn2+. 4 Zn2+ increased the frequency of m.e.p.ps in K+-free (replaced with NaCl) solution. The effect appeared with shorter latency in this solution compared to the standard Krebs-Ringer solution. 5 The effect of Zn2+ was partially antagonized by dantrolene sodium or by neomycin. Both agents also reduced the effect of external Ca2+ on m.e.p.ps in depolarizing solution. 6 Cd2+ and 2,3-bisphosphoglycerate also elevated the frequency of m.e.p.ps in a manner independent of external Ca2+, but the latter compound was much less potent than Cd2+. 7 These experiments provide evidence for a role of intracellularly stored Ca2+ in the release of transmitter at the motor nerve terminal. The release of Ca2+ from the storage site may be coupled with the metabolism of phosphatidylinositol.