ENGINEERED CHANNELS FOR STUDY OF PCP ACTION

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The relationship between NMDA receptor structure and phencyclidine (PCP) sensitivity will be examined, using techniques to express cloned channels in an oocyte system, and monitoring the function of the expressed elements with electrophysiological techniques. We will use four splice variants, with known amino acid sequences, of the NMDAR1 receptor/channel subunit which we have isolated from rat brain to relate differences in the structure, of their products with differences in various parameters of PCP sensitivity. In particular, we will determine the role which particular amino acid sequences which are either present or absent in the spice variants play in the characteristics of NMDA activation of the receptor/channel and the associated modulation of receptor/channel activity by PCP. The presence or absence of the amino acid sequences which comprise the spliced cassettes render the splice variants considerably different with respect to charge distribution of the receptor protein, and these differences are likely to affect PCP actions. The consequences of the presence or absence of characteristics such as desensitization for PCP action will be explored. This work, which is primarily a pilot study, will determine the usefulness of this particular preparation for the investigation of PCP action, and will provide the background information necessary to devise intelligent mutagenesis experiments in the future.