NR2 subunit-dependence of NMDA receptor channel block by external Mg2+.
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.
Qian
Anqi
A
Department of Neuroscience, 446 Crawford Hall, University of Pittsburgh, Pittsburgh, PA 15260, USA.
Buller
Amy L
AL
Johnson
Jon W
JW
D000465:Algorithms; D000818:Animals; D002460:Cell Line; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004558:Electric Stimulation; D004594:Electrophysiology; D018691:Excitatory Amino Acid Antagonists; D006801:Humans; D007700:Kinetics; D008274:Magnesium / Q000494:pharmacology*; D008564:Membrane Potentials / Q000502:physiology; D018408:Patch-Clamp Techniques; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012996:Solutions; D014162:Transfection
D018691:Excitatory Amino Acid Antagonists; C409466:NR1 NMDA receptor; C120997:NR2A NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D012996:Solutions; D008274:Magnesium