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J. Biol. Chem., Vol. 282, Issue 26, 19062-19070, June 29, 2007

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Transcriptional Repression by a Conserved Intronic Sequence in the Nicotinic Receptor 3 Subunit Gene^*

From the Brudnick Neuropsychiatric Research Institute, Department of Psychiatry, the University of Massachusetts Medical School, Worcester, Massachusetts 01604

The genes encoding the nicotinic acetylcholine receptor 3, 5, and 4 subunits are genomically clustered. These genes are co-expressed in a variety of cells in the peripheral and central nervous systems. Their gene products assemble in a number of stoichiometries to generate several nicotinic receptor subtypes that have distinct pharmacological and physiological properties. Signaling through these receptors is critical for a variety of fundamental biological processes. Despite their importance, the transcriptional mechanisms underlying their coordinated expression remain to be completely elucidated. By using a bioinformatics approach, we identified a highly conserved intronic sequence within the fifth intron of the 3 subunit gene. Reporter gene analysis demonstrated that this sequence, termed "3 intron 5," inhibits the transcriptional activities of the 3 and 4 subunit gene promoters. This repressive activity is position- and orientation-independent. Importantly, repression occurs in a cell type-specific manner, being present in cells that do not express the receptor genes or expresses them at very low levels. Electrophoretic mobility shift assays demonstrate that nuclear proteins specifically interact with 3 intron 5 at two distinct sites. We propose that this intronic repressor element is important for the restricted expression patterns of the nicotinic receptor 3 and 4 subunit genes.

Received for publication, March 19, 2007 , and in revised form, May 1, 2007.

^* This work was supported in part by National Institutes of Health Grant NS30243, Philip Morris USA Inc., and Philip Morris International. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, 303 Belmont St., Worcester, MA 01604. Tel.: 508-856-4035; Fax: 508-856-4130; E-mail: paul.gardner{at}umassmed.edu.

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