The role of divalent cations in the N‐methyl‐D‐aspartate responses of mouse central neurones in culture.

Abstract

1. Single-channel currents activated by N-methyl-D-aspartate (NMDA) agonists were analysed in the presence of various extracellular concentrations of divalent cations in outside-out patches from mouse neurones in primary culture. 2. In nominally Mg2+-free solutions the opening and closing of the channels leads to rectangular current pulses, the mean duration of which varies little with membrane potential. After addition of Mg2+, the single-channel currents recorded at negative potentials appear in bursts of short openings separated by brief closures. 3. The duration of the short openings decreases with increasing Mg2+ concentration, while the duration of the short closures is independent of the Mg2+ concentration. Depolarization increases the duration of the short openings and decreases the duration of the short closures. 4. The dependence of the burst structure on the Mg2+ concentration and on membrane potential is compatible to a first approximation with a model in which Mg2+ ions enter the open channel and block it by binding at a deep site. A better approximation requires, however, additional assumptions such as Mg2+ permeation and/or interactions between Ca2+ and Mg2+. 5. Increasing the extracellular Ca2+ concentration from 1 to 100 mM produces three effects on the currents flowing through NMDA channels. It shifts the reversal potential towards a positive value (+30 mV); it reduces the outward current flowing through the NMDA channels at very positive potentials; it reduces the inward current flowing at negative potentials. 6. The interpretation of the effects of Ca2+ appears to require three hypotheses: that Ca2+ permeates the NMDA channel, that there exists a significant surface potential at the entrance of the NMDA channel in physiological solutions and that both Ca2+ and monovalent cations bind to the channel, binding being stronger in the case of Ca2+ ions. 7. While Co2+ and, to a lesser extent, Mn2+ mimic the effects of Mg2+ on the NMDA channel, Ca2+, Ba2+ and Cd2+ do not. The distinction between Mg2+-like and Ca2+-like divalent cations corresponds to a difference in the speed of exchange of the water molecules surrounding the cations in solutions. Thus, it is possible that permeation occurs for all the divalent cations, but is slower for those which are slowly dehydrated.

Ethanol potentiates and blocks NMDA‐activated single‐channel currents in rat hippocampal pyramidal cells

“…It is possible that these are characteristics of the NMDA-activated channels, themselves, but we cannot discard the possibility that this behavior could be due to an open channel blockade. NMDA could be blocking its own channels, or we could be seeing a blockade by Mg2+ [22]. Values for mean open time for a given holding potential were constant at the different concentrations of NMDA used in these experiments, arguing against the possibility that NMDA is acting as an open channel blocker.…”

Biophysical model of a Hebbian synapse.

“…The associated channel is voltage-dependent due to block by Mg2`that is relieved by membrane depolarization (17)(18)(19).…”

Behavioral and neuropharmacological characterization of nicotine as a conditional stimulus

“…Postsynaptic N-methyl-D-aspartate receptors are only activated when glutamate binds to its site on the receptor and the cell membrane has suffi ciently depolarized to remove Mg 2+ from blocking the receptor channel, and therefore serve to combine chemical and electrical messaging (Ascher andNowak, 1988 andKiss et al, 1994). Glutamate release via nicotinic acetylcholine receptor stimulation ultimately activates N-methyl-Daspartate receptors, increasing ventral tegmental area dopaminergic burst fi ring into the nucleus accumbens (Schilström et al, 2003 andSchilström et al, 2004).…”