NR2 subunit-dependence of NMDA receptor channel block by external Mg2+

J Physiol. 2005 Jan 15;562(Pt 2):319-31. doi: 10.1113/jphysiol.2004.076737. Epub 2004 Oct 28.

Abstract

The vital roles played by NMDA receptors in CNS physiology depend critically on powerful voltage-dependent channel block by external Mg(2+) (Mg(2+)(o)). NMDA receptor channel block by Mg(2+)(o) depends on receptor subunit composition: NR1/2A receptors (receptors composed of NR1 and NR2A subunits) and NR1/2B receptors are more strongly inhibited by Mg(2+)(o) than are NR1/2C or NR1/2D receptors. We investigated the effects of Mg(2+)(o) on single-channel and whole-cell currents recorded from recombinant NR1/2D and NR1/2A receptors expressed in HEK293 and 293T cells. The main conclusions are as follows: (1) Voltage-dependent inhibition by Mg(2+)(o) of whole-cell NR1/2D receptor responses was at least 4-fold weaker than inhibition of NR1/2A receptor responses at all voltages tested. (2) Channel block by Mg(2+)(o) reduced the duration of NR1/2D receptor single-channel openings; this reduction was used to estimate the apparent blocking rate of Mg(2+)(o) (k(+,app)). The k(+,app) for NR1/2D receptors was similar to but moderately slower than the k(+,app) obtained from cortical NMDA receptors composed of NR1, NR2A and NR2B subunits at all voltages tested. (3) Mg(2+)(o) blocking events induced an additional component in the closed-duration distribution; this component was used to estimate the apparent unblocking rate of Mg(2+)(o) (k(-,app)). The k(-,app) for NR1/2D receptors was much faster than the k(-,app) for cortical receptors at all voltages tested. The voltage-dependence of the k(-,app) of NR1/2D and cortical receptors differed in a manner that suggested that Mg(2+)(o) may permeate NR1/2D receptors more easily than cortical receptors. (4) Mg(2+)(o) inhibits NR1/2D receptors less effectively than cortical receptors chiefly because Mg(2+)(o) unbinds much more rapidly from NR1/2D receptors.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Algorithms
  • Animals
  • Cell Line
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / metabolism
  • Electric Stimulation
  • Electrophysiology
  • Excitatory Amino Acid Antagonists*
  • Humans
  • Kinetics
  • Magnesium / pharmacology*
  • Membrane Potentials / physiology
  • Patch-Clamp Techniques
  • Rats
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Solutions
  • Transfection

Substances

  • Excitatory Amino Acid Antagonists
  • NR1 NMDA receptor
  • NR2A NMDA receptor
  • Receptors, N-Methyl-D-Aspartate
  • Solutions
  • Magnesium