Tetanic stimulation increases the frequency of miniature end-plate potentials at the frog neuromuscular junction in Mn2+-, CO2+-, and Ni2+-saline solutions.

The effects of Mn2+, Co2+, and of Ni2+ on quantal acetylcholine (ACh) release have been studied with conventional microelectrode techniques. Increasing the [Co2+]0 or [Ni2+]0 (in the absence of extracellular Ca2+) caused an increase in miniature endplate potential (MEPP) frequency. [Mn2+]0 caused some increase in frequency at low levels, but then there was no rise as the concentration was increased further. In preparations depolarized with 20 mM K+, the MEPP frequency was a monotonically increasing function of [Co2+]0 or [Ni2+]0. In increasing concentrations of [Mn2+]0 there was an increase followed by a levelling off or a depression at higher concentrations. Tetanic stimulation of the motor nerve in solutions containing no added divalent cations or containing MgEGTA produced slight or no increases in MEPP frequency. In Mn2+-, Co2+- or Ni2+- saline solution stimulation of the motor nerve led to substantial increases in MEPP frequencies. The maximum frequency attained in Mn2+, Co2+, or Ni2+ was a power function of: (a) the duration of the tetanus; (b) the frequency of stimulation during the tetanus; or (c) the extracellular concentration of the divalent cation. During stimulation in Mn2+-saline solution the MEPP frequency reached a maximum; further stimulation led to a fall in frequency. We conclude that Mn2+, Co2+, and Ni2+ can enter the nerve terminal through a voltage-gated channel. Once within the terminal, they can stimulate quantal release by releasing Ca2+ or by causing the liberation of an activator, like H+, within the terminal.