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Background  The plasma membrane Na + /Ca 2+ -exchanger (NCX) has recently been shown to regulate Ca 2+ -dependent  N -methyl- d -aspartate receptor (NMDAR) desensitization, suggesting a tight interaction of NCXs and NMDARs in lipid nanoclasters or “rafts”. To evaluate possible role of this interaction we studied effects of Li +  on NMDA-elicited whole-cell currents and Ca 2+  responses of rat cortical neurons in vitro before and after cholesterol extraction by methyl-β-cyclodextrin (MβCD).    Results  Substitution Li +  for Na +  in the external solution caused a concentration-dependent decrease of steady-state NMDAR currents from 440 ± 71 pA to 111 ± 29 pA in 140 mM Na +  and 140 mM Li + , respectively. The Li +  inhibition of NMDAR currents disappeared in the absence of Ca 2+  in the external solution (Ca 2+ -free), suggesting that Li +  enhanced Ca 2+ -dependent NMDAR desensitization. Whereas the cholesterol extraction with MβCD induced a decrease of NMDAR currents to 136 ± 32 pA in 140 mM Na +  and 46 ± 15 pA in 140 mM Li + , the IC 50  values for the Li +  inhibition were similar (about 44 mM Li + ) before and after this procedure. In the Ca 2+ -free Na +  solution the steady-state NMDAR currents after the cholesterol extraction were 47 ± 6% of control values. Apparently this amplitude decrease was not Ca 2+ -dependent. In the Na +  solution containing 1 mM Ca 2+  the Ca 2+ -dependent NMDAR desensitization was greater when cholesterol was extracted. Obviously, this procedure promoted its development. In agreement, Li +  and KB-R7943, an inhibitor of NCX, both considerably reduced NMDA-activated Ca 2+  responses. The cholesterol extraction itself caused a decrease of NMDA-activated Ca 2+  responses and, in addition, abolished the effects of Li +  and KB-R7943. The cholesterol loading into the plasma membrane caused a recovery of the KB-R7943 effects.    Conclusions  Taken together our data suggest that NCXs downregulate the Ca 2+ -dependent NMDAR desensitization. Most likely, this is determined by a tight functional interaction of NCX and NMDAR molecules because of their co-localization in membrane lipid rafts. The destruction of these rafts is accompanied by an enhancement of NMDAR desensitization and a loss of NCX-selective agent effects on NMDARs.

Downregulation of calcium-dependent NMDA receptor desensitization by sodium-calcium exchangers: a role of membrane cholesterol