NR2 subunit-depenclence 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 Mg2+ (Mg-o(2+)). NMDA receptor channel block by Mg-o(2+) 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-o(2+) than are NR1/2C or NR1/2D receptors. We investigated the effects of Mg-o(2+) on single-channel 0 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-o(2+) 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-o(2+) reduced the duration of NR1/2D receptor single-channel openings; this reduction was used to estimate the apparent blocking rate of Mg-o(2+)(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-o(2+) blocking events induced an additional component in the closed-duration distribution; this component was used to estimate the apparent unblocking rate of Mg-o(2+) (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-o(2+) may permeate NR1/2D receptors more easily than cortical receptors. (4) Mg-o(2+) inhibits NR1/2D receptors less effectively than cortical receptors chiefly because Mg-o(2+) unbinds much more rapidly from NR1/2D receptors.