Effects of Sodium and Calcium Channel Blockade on the Increase in Spontaneous Transmitter Release Produced by the Mitochondrial Inhibitor, Dinitrophenol

Document Type

Article

Publication Date

1-1-1988

Description

The effect of 2,4-dinitrophenol (DNP) was investigated at the frog neuromuscular junction to elucidate the mechanism by which mitochondrial inhibitors increase transmitter release. After a prolonged lag time (30 min), DNP (10-4 M) caused an increase in miniature endplate potential frequency (MEPP F), which peaked within 10 min and then declined toward, but not reaching, control values. The time course and peak effects of the response were not altered by Na and Ca channel blockade [produced by 3 μM tetrodotoxin (TTX) plus 1.8 mM Co++], but the lag time was significantly shortened (5 min). The [TTX plus Co++] used was sufficient to prevent influx of ions at the terminal, as the same concentration caused complete block of a 50-fold MEPP F increase to 15 mM [K+]. The results suggest that mitochondrial inhibitors produce their effect primarily by reversing the Ca++ uniporter and not by a Na+-mediated stimulation of the Na+-Ca++ antiporter. Their mechanism in this regard differs from that underlying the MEPP F increase produced by cardiac glycosides. The long lag time with DNP may be due to Na pump inhibition and nerve terminal swelling, and the shortening of lag time by TTX plus Co++ to an inhibition of Na+ influx and swelling. Finally, the block of MEPP F with TTX plus Co++ indicates that the MEPP F increase with Co++ alone is probably due to entry of Co++ through unblocked Na channels.

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