N-methyl-D-aspartate (NMDA) receptors are an important subset of glutamate receptors and are found throughout the mammalian central nervous system. Studies during the past several years have found roles for these receptors in a variety of physiologic processes, including long-term potentiation and learning. NMDA receptors also figure prominently in pathological phenomena such as hypoxic-ischemic damage and epilepsy. Activation of these receptors by NMDA and other amino acids occurs only in the presence of glycine. In addition to allowing receptor activation, glycine apparently affects receptor desensitization. The rapidity and extent of NMDA receptor desensitization suggests that this process might have a modulatory role in some physiological (and pathological) phenomena. The long-term goal of the proposed research is a mechanistic understanding of the modulation of receptor activation and desensitization by the co-agonists NMDA and glycine, and an understanding of the effects of amino acid agonists and antagonists. The primary experimental approach is to record NMDA receptor single- channel currents from rat brain hippocampal and cortical neurons.Analysis of the open and shut intervals obtained from channels in the presence in the presence of various concentrations of NMDA/glycine will provide information about the minimal number of kinetic open and closed states. Detailed analysis of the long shut intervals will provide important information about desensitization, and how this process is affected by NMDA and glycine. A similar analysis of channel activation and desensitization will be performed upon currents obtained in the presence of the putative neurotransmitters homocysteate and aspartate, and also in the presence of receptor antagonists. Proposed experiments will also examine how channel kinetics are affected by the sequence in which NMDA and glycine are applied. Experiments in which certain kinetic transitions are sought will provide highly specific information about the underlying mechanism of NMDA/glycine effects. For example, the openings that bracket the desensitized shut intervals will be examined to determine if any particular open state serves as a gateway to desensitization. Another approach, adjacent states analysis, searches for relationships between the durations of successive openings and closings.
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