REGULATION OF NEURONAL ACETYLCHOLINE RECEPTOR GENES

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Neuronal nicotinic acetylcholine receptors (nAChRs) are composed of binding (alpha) and structural (beta) subunits. Different combinations of alpha and beta subunits produce nAChR subtypes with different pharmacological and ion conducting properties. Transcriptional regulation may be an important determinant of receptor subtype in a neuronal population and thus influence transmission through a ganglia or group of neurons in the CNS by controlling the nAChR subtype(s) present. We have chosen to focus on the regulation of the alpha3 and alpha4 genes because they represent, respectively, the predominant ganglionic and CNS ligand binding subunit genes; they both have been shown to be regulated at the RNA level by cell contact or factors such as NGF and TPA; and in the case of the rat alpha3, cell-specificity is regulated at least in part at the transcriptional level. The alpha3 and alpha4 promoters will be identified and sequenced. PC12 cells will be used for biochemical and molecular genetic studies to identify DNA-binding proteins that interact with the alpha3 promoter and may be involved in the control of nAChR gene expression. Rat superior cervical ganglion (SCG) neurons will be used to complement the promoter and transcription factor studies in an examination of the effects of nicotine, NGF, TPA and cell-cell contact on the expression of several nAChR subunit genes. An understanding of how these nAChR genes are regulated and the expression of subtypes controlled, will lead to insight into how nicotine produces effects in the nervous system. The mechanisms that control the expression of these genes may also be relevant to control of neuronal nAChR gene expression elsewhere in the nervous system and for other members of this multigene family.