Na(+)-Ca(2+) exchanger controls the gain of the Ca(2+) amplifier in the dendrites of amacrine cells.

We have previously shown that disabling forward-mode Na(+)-Ca(2+) exchange in amacrine cells greatly prolongs the depolarization-induced release of transmitter. To investigate the mechanism for this, we imaged [Ca(2+)](i) in segments of dendrites during depolarization. Removal of [Na(+)](o) produced no immediate effect on resting [Ca(2+)](i) but did prolong [Ca(2+)](i) transients induced by brief depolarization in both voltage-clamped and unclamped cells. In some cells, depolarization gave rise to stable patterns of higher and lower [Ca(2+)] over micrometer-length scales that collapsed once [Na(+)](o) was restored. Prolongation of [Ca(2+)](i) transients by removal of [Na(+)](o) is not due to reverse mode operation of Na(+)-Ca(2+) exchange but is instead a consequence of Ca(2+) release from endoplasmic reticulum (ER) stores over which Na(+)-Ca(2+) exchange normally exercises control. Even in normal [Na(+)](o), hotspots for [Ca(2+)] could be seen following depolarization, that are attributable to local Ca(2+)-induced Ca(2+) release. Hotspots were seen to be labile, probably reflecting the state of local stores or their Ca(2+) release channels. When ER stores were emptied of Ca(2+) by thapsigargin, [Ca(2+)] transients in dendrites were greatly reduced and unaffected by the removal of [Na(+)](o) implying that even when Na(+)-Ca(2+) exchange is working normally, the majority of the [Ca(2+)](i) increase by depolarization is due to internal release rather than influx across the plasma membrane. Na(+)-Ca(2+) exchange has an important role in controlling [Ca(2+)] dynamics in amacrine cell dendrites chiefly by moderating the positive feedback of the Ca(2+) amplifier.