NA-CA2+ EXCHANGE CURRENTS IN CORTICAL-NEURONS - CONCOMITANT FORWARD AND REVERSE OPERATION AND EFFECT OF GLUTAMATE()

Na+-Ca2+ exchanger-associated membrane currents were studied in cultur ed murine neocortical neurons, using whole-cell recording combined wit h intracellular perfusion. A net inward current specifically associate d with forward (Na-o(+)-Ca-i(2+)) exchange was evoked at -40 mV by swi tching external 140 mM Li+ to 140 mM Na+. The voltage dependence of th is current was consistent with that predicted for 3Na(+):1Ca(2+) excha nge. As expected, the current depended on internal Ca2+, and could be blocked by intracellular application of the exchanger inhibitory pepti de, XIP. Raising internal Na+ from 3 to 20 mM or switching the externa l solution from 140 mM Li+ to 30 mM Na+ activated outward currents, co nsistent: with reverse (Na-i(+)-Ca-o(2+)) exchange. An external Ca2+- sensitive current was also identified as associated with reverse Na+-C a2+ exchange based on its internal Na+ dependence and sensitivity to X IP. Combined application of external Na+ and Ca2+ in the absence of in ternal Na+ triggered a 3.3-fold larger inward current than the current activated in the presence of 3 mM internal Nat raising the intriguing possibility that Na+-Ca2+ exchangers might concurrently operate in bo th the forward and the reverse direction, perhaps in different subcell ular locations. With this idea in mind, we examined the effect of exci totoxic glutamate receptor activation on exchanger operation. After 3- 5 min of exposure to 100-200 mu M glutamate, the forward exchanger cur rent was significantly increased even when external Na+ was reduced to 100 mM, and the external Ca2+-activated reverse exchanger current was eliminated.