MOLECULAR BIOLOGY OF NEUROTRANSMITTER RECEPTORS

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This project is to characterize the gene and protein structure and evolution of neurotransmitter receptors belonging to two major multigene families. The gene families are those comprising adrenergic, muscarinic, opsin, serotonin and octopamine receptors, among others; and the second family comprising nicotinic cholinergic, GABA/benzodiazepine, NMDA, and glycine receptors. The specific aims are: to clone and sequence the genes for receptors in these two multigene families; to obtain high-density receptor expression and to use the expressed proteins to determine the complete receptor structure, in part by computer enhanced molecular modeling; to determine the evolution of the neurotransmitter receptor gene families; and to search for and characterize receptor gene polymorphisms. To date we have cloned and sequenced a significant number of receptor genes from both multigene families. These include several alpha and beta-adrenergic receptors from human and rat cDNA and genomic libraries; muscarinic cholinergic receptors from human, rat, and Drosophila genomic libraries; octopamine receptors from Drosophila; and nicotinic receptors from locusts and C. elegans. Most recently, we have cloned and sequenced the human GABA-A receptor beta- 1 and beta-3 subunits, a rat m3 muscarinic receptor genomic clone, the rat fat cell-specific (beta-3) adrenergic receptor, several C. elegans nicotinic receptor subunits, and an as yet unidentified 7-transmembrane receptor from Drosophila. In addition, more than a dozen receptor clones have been isolated in our human brain cDNA project [ZO1 NS02806-02], including the N-formylpeptide receptor, the cannabinoid receptor, and the alpha-2B-adrenergic receptor. A major finding has been the discovery that the human GABA beta-3 subunit gene lies in the locus of Prader-Willi syndrome and Angleman Syndrome on chromosome 15.