The molecular basis of neurotransmission in the CNS will be studied by isolating genes encoding neurotransmitter receptors and using them to study the regulation of neuronal excitability. A long-term goal of the work is to understand the means by which ionic conductances are affected by binding of neurotransmitters to their receptors. Two types of neurotransmitters that play different roles in the CNS, glutamate and neuropeptide transmitters, will be the focus of this work. Glutamate is the primary excitatory neurotransmitter utilized by CNS neurons and plays a central role in initiating the depolarization of neurons. Regulation of glutamate release and subsequent signal transduction by the receptor are crucial points at which neuronal excitability can be regulated. The second type of neurotransmitter whose receptors we are studying are the neuropeptide transmitters. The actions of neuropeptides are characteristically slow in onset and relatively long-lasting. This time course is characteristic of receptors that mediate their effects by coupling to intracellular G proteins. The strategy in this proposal is to use both homology-based and expression-cloning approaches to isolate genes coding for receptors in these two groups, and to use the cloned genes to generate nucleic acid and antibody probes to study the expression, localization and function of the receptors. These studies combine molecular approaches with functional analyses of receptor action as measured on the single-cell level by electrophysiological methodologies, and in populations of cells by cell biological and biochemical techniques. The work in this proposal will contribute to our knowledge about the molecular components involved in synaptic transmission and their mechanisms of action, which have important implications for the understanding of memory, learning, and the pathology of neurodegenerative diseases.
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