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Inhibition of Mitochondrial Ca²⁺ Uptake Affects Phasic Release From Motor Terminals Differently Depending on External [Ca²⁺]

Department of Physiology and Biophysics, University of Miami School of Medicine, Miami, Florida 33136

Submitted 8 January 2003; accepted in final form 24 March 2003

We investigated how inhibition of mitochondrial Ca²⁺ uptake affects stimulation-induced increases in cytosolic [Ca²⁺] and phasic and asynchronous transmitter release in lizard motor terminals in 2 and 0.5 mM bath [Ca²⁺]. Lowering bath [Ca²⁺] reduced the rate of rise, but not the final amplitude, of the increase in mitochondrial [Ca²⁺] during 50-Hz stimulation. The amplitude of the stimulation-induced increase in cytosolic [Ca²⁺] was reduced in low-bath [Ca²⁺] and increased when mitochondrial Ca²⁺ uptake was inhibited by depolarizing mitochondria. In 2 mM Ca²⁺, end-plate potentials (epps) depressed by 53% after 10 s of 50-Hz stimulation, and this depression increased to 80% after mitochondrial depolarization. In contrast, in 0.5 mM Ca²⁺ the same stimulation pattern increased epps by 3.4-fold, and this increase was even greater (transiently) after mitochondrial depolarization. In both 2 and 0.5 mM [Ca²⁺], mitochondrial depolarization increased asynchronous release during the 50-Hz train and increased the total vesicular release (phasic and asynchronous) measured by destaining of the styryl dye FM2-10. These results suggest that by limiting the stimulation-induced increase in cytosolic [Ca²⁺], mitochondrial Ca²⁺ uptake maintains a high ratio of phasic to asynchronous release, thus helping to sustain neuromuscular transmission during repetitive stimulation. Interestingly, the quantal content of the epp reached during 50-Hz stimulation stabilized at a similar level (20 quanta) in both 2 and 0.5 mM Ca²⁺. A similar convergence was measured in oligomycin, which inhibits mitochondrial ATP synthesis without depolarizing mitochondria, but quantal contents fell to <20 when mitochondria were depolarized in 2 mM Ca²⁺.

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