Roles for mitochondrial and reverse mode Na+/Ca2+ exchange and the plasmalemma Ca2+ ATPase in post-tetanic potentiation at crayfish neuromuscular junctions.

We have explored the processes regulating presynaptic calcium concentration ([Ca(2+)](i)) in the generation of post-tetanic potentiation (PTP) at crayfish neuromuscular junctions, using spectrophotometric dyes to measure changes in [Ca(2+)](i) and [Na(+)](i) and effects of inhibitors of Ca(2+)-transport processes. The mitochondrial Na(+)/Ca(2+) exchange inhibitor CGP 37157 was without effect, whereas the reverse mode plasmalemmal Na(+)/Ca(2+) exchange inhibitor KB R7943 reduced PTP and Ca(2+) accumulation caused by increased [Na(+)](i). Exchange inhibitory peptide and C28R2 had opposite effects, consistent with their block of the plasma membrane Ca(2+) ATPase. All drugs except CGP 37157 reduced Ca(2+) accumulation caused by Na(+) accumulation, which occurred on block of the Na(+)/K(+) pump, acting in proportion to their effects on plasmalemmal Na(+)/Ca(2+) exchange. We find no role for mitochondrial Na(+)/Ca(2+) exchange in presynaptic Ca(2+) regulation. The plasma membrane Na(+)/Ca(2+) exchanger acts in reverse mode to admit Ca(2+) into nerve terminals during and for some minutes after tetanic stimulation, while at the same time the plasma membrane Ca(2+) ATPase operates as an important Ca(2+) removal process. The interplay of these two Ca(2+) transport processes with Na(+)-independent mitochondrial Ca(2+) fluxes and the plasmalemma Na(+)/K(+) pump determines the magnitude of tetanic [Ca(2+)](i) accumulation and potentiation of excitatory transmission, and the post-tetanic time courses of decay of elevated [Ca(2+)](i) and PTP.