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.