This section investigates the mechanism of action of excitatory amino acids in the vertebrate CNS, utilizing electrophysiological techniques. Fast perfusion systems are used for concentration jump application of agonists and antagonists to nerve cells and membrane patches under voltage clamp. Responses at NMDA receptors are modulated by the polyamine spermine via three mechanisms of action: An increase in affinity for glycine, an increase in maximal response at saturating concentrations of glycine, voltage-dependent block. Kinetic experiments with different glycine site agonists provide evidence for a rapid allosteric potentiating action of spermine. Calcium ions regulate NMDA receptor activity via an intracellular site of action, and produce reversible inactivation, and enhanced desensitization. The kinetics of action of glutamate at AMPA preferring receptors was studied with a piezoelectric device capable of making solution changes within 200 micros. The decay of responses following 1 ms pulse application of glutamate was 3 times faster than the onset of desensitization recorded with step applications lasting 10 or 100 ms. even though up to 50% desensitization developed following 1 ms applications. The pharmacology of kainate preferring receptors was studied in DRG neurons, in which willardiine analogues act with a potency sequence the inverse of that at AMPA receptors.
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