Modulation by permeant ions of Mg(2+) inhibition of NMDA-activated whole-cell currents in rat cortical neurons.
Whole-cell N-methyl-D-aspartate (NMDA)-activated currents were recorded from cultured rat cortical neurons. We report here a powerful effect of changing permeant ion concentrations on the voltage-dependent inhibition by external Mg(2+) (Mg(2+)(o)) of these currents. Internal Cs(+) (Cs(+)(i)) affected Mg(2+)(o) inhibition of the NMDA-activated currents in a voltage-dependent manner. A decrease in Cs(+)(i) concentration ([Cs(+)](i)) from 125 to 8 mM reduced Mg(2+)(o) IC(50) by 1.4-fold at -105 mV and by 11.5-fold at -15 mV. A decrease in external Na(+) (Na(+)(o)) concentration ([Na(+)](o)) also reduced Mg(2+)(o) IC(50). This effect was voltage independent. A decrease in [Na(+)](o) from 140 to 70 mM reduced Mg(2+)(o) IC(50) by 1.4-fold at -105 mV and by 1.6-fold at -15 mV. Varying external Ca(2+) (Ca(2+)(o)) concentrations ([Ca(2+)](o)) from 0.1 to 1 mM did not affect Mg(2+)(o) inhibition, even though changing [Ca(2+)](o) in the same range strongly influenced the magnitude of NMDA-activated currents in the absence of Mg(2+)(o). However, increasing [Ca(2+)](o) to higher concentrations (2-20 mM) greatly increased Mg(2+)(o) IC(50) at hyperpolarized voltages. These data are consistent with a model in which Na(+)(i) and Cs(+)(i) modulate Mg(2+)(o) inhibition of NMDA-activated currents by occupying external permeant ion binding sites. The Mg(2+)(o) IC(50) values reported here are similar to Mg(2+)(o) K(D) values calculated from previous single-channel measurements of Mg(2+)(o) blocking kinetics. This similarity implies that Mg(2+)(o) does not affect gating while blocking the channel.
Qian
Anqi
A
Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260, USA.
Antonov
Sergei M
SM
Johnson
Jon W
JW
D000818:Animals; D002118:Calcium / Q000494:pharmacology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D002586:Cesium / Q000494:pharmacology; D004553:Electric Conductivity; D007477:Ions; D008274:Magnesium / Q000494:pharmacology*; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors* / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D009994:Osmolar Concentration; D010539:Permeability; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000494:pharmacology
D007477:Ions; D002586:Cesium; D016202:N-Methylaspartate; D012964:Sodium; D008274:Magnesium; D002118:Calcium