Interaction of Mg²⁺ and phencyclidine in use-dependent block of NMDA channels

The interaction between Mg²⁺ and phencyclidine (PCP) in blocking open N-methyl-d-aspartate (NMDA) channels was investigated in Xenopus oocytes injected with rat brain mRNA. These receptors exhibit the pharmacological and physiological properties of the neuronal receptors, and the oocyte is readily amenable to electrical recording and application of well-controlled chemical stimuli. We found that Mg²⁺ at physiological concentrations greatly impeded the ability of PCP to block the NMDA channel. The interaction between Mg²⁺ and PCP was competitive; 0.5 mM Mg²⁺ caused a four-fold decrease in the potency of PCP in blocking open NMDA channels. Moreover, Mg²⁺ speeded the recovery from PCP block in the presence of agonist, suggesting that Mg²⁺ reduced reblock of NMDA channels by PCP that had escaped from open channels. Our observations suggest that the presence of Mg²⁺ in the channel tends to prevent PCP entry and block. Since depolarization is likely to reduce channel occupancy by Mg²⁺ more than that by PCP, neural activity may have an important influence on the actions of PCP and related drugs.