Permeant ion regulation of N -methyl- d -aspartate receptor channel block by Mg ²⁺

Abstract

Block of the channel of N-methyl-D-aspartate (12,(19)(20)(21)(22). The M2 region is a pore loop that enters and exits the membrane intracellularly and is believed to form a large portion of the channel of NMDA receptors. A physical location of the Mg o 2ϩ -blocking site near the external tip of the M2 region appears inconsistent with an electrical location near the internal extreme of the channel.One mechanism by which the voltage dependence of block by -binding sites deep in the channel (19) and on the external side of the channel (10, 27) and for permeant monovalent cation-binding sites on both sides of the channel (26). We recently demonstrated that occupation of the permeant monovalent cation-binding sites has a profound effect on the blocking kinetics of two adamantane derivatives that block the channel of NMDA receptors (26). Here, we examine how occupation of these permeant monovalent cation-binding sites influences block by Mg o 2ϩ . Experimental ProceduresPreparation and Solutions. Primary cultures of rat cortical neurons were prepared from 16-day embryos as described (28). Neurons were used for experiments after 15-30 days in culture.Recordings of single-channel currents were performed by using outside-out patches (29) at room temperature (21-23°C). Pipettes were filled with one of three solutions. The control (130

Effects of antenatal magnesium sulfate treatment for neonatal neuro-protection on cerebral oxygen kinetics

“…The mean (SD) age of the infants at time of the initial NIRS and cranial ultrasound study was 11 (6) hours for the nonexposed group and 12 (7) hours for the MgSO 4 group. While four infants had cranial ultrasound evidence of P/IVH at the time of the NIRS study (all unilateral grade 1 IVH), fewer infants in the MgSO 4 group (n = 4) were diagnosed with P/IVH (all grades) compared to those not exposed to MgSO 4 (n = 9) by 72 h of life (P = 0.03).…”

“…Proposed mechanisms by which MgSO 4 exerts a neuroprotective effect include effects on the cardiovascular system through its role in the regulation of vascular tone (6), cerebral metabolism including prevention of excess glutamate release (7), and reductions in systemic proinflammatory cytokine production (8). The effect of antenatal MgSO 4 administration on the neonatal systemic and cerebral vasculature is unclear.…”

Direct Effects of Calmodulin on NMDA Receptor Single-Channel Gating in Rat Hippocampal Granule Cells

“…This suggests that an allosteric rather than a channelblocking (Zhang et al, 1998) mechanism is involved in inhibition of single NMDA channel activity by calmodulin. For example, characteristic NMDA channel block, such as that observed with magnesium, is recognized by a distinct fingerprint alteration of the single-channel shut-time distribution (Ascher and Nowak, 1988;Antonov and Johnson, 1999). Because magnesium does not change the time course of NMDA receptor-mediated synaptic currents (Hestrin et al, 1990a), it is likely that a similar effect of calmodulin on the duration of channel activations will be observed at physiological magnesium concentrations (although the actions of calmodulin on channel open time would then be obscured by the much more rapid channel-blocking action of magnesium).…”

Permeant Ion Effects on External Mg2+Block of NR1/2D NMDA Receptors

“…Mg o 2ϩ inhibition of NMDA receptors varies with brain region and developmental stage because of differential NR2 subunit expression coupled with NR2 subunit dependence of Mg o 2ϩ inhibition (Kato and Yoshimura, 1993;Monyer et al, 1994;Momiyama et al, 1996;Qian et al, 2005). The degree and voltage dependence of Mg o 2ϩ inhibition are powerfully modulated by permeant ions (Antonov and Johnson, 1999;Zhu and Auerbach, 2001a,b;Qian et al, 2002). Along with its mechanistic importance, permeant ion modulation of Mg o 2ϩ inhibition is likely to participate in nervous system physiology and pathology.…”

“…Changes in permeant ion concentration likely act in concert with other modulatory mechanisms (Chen and Huang, 1992;Zhang et al, 1996;Guo and Huang, 2001) to alter Mg o 2ϩ inhibition in pathological states. Permeant ion effects on Mg o 2ϩ inhibition have been investigated for NMDA receptors that contain NR2A or NR2B subunits (Antonov and Johnson, 1999;Zhu and Auerbach, 2001a,b;Qian et al, 2002), but not for receptors that contain NR2C or NR2D subunits. Understanding permeant ion effects on Mg o 2ϩ inhibition of NR1/2D receptors, which play important physiological roles developmentally and in adults (Okabe et al, 1998;Bengzon et al, 1999;Hrabetova et al, 2000;Miyamoto et al, 2002; Thompson et al, 2002), would deepen insight into blocking mechanisms and their variation among NMDA receptor subtypes.…”