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J. Biol. Chem., Vol. 283, Issue 14, 9328-9340, April 4, 2008

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Surface Expression of GABA_A Receptors Is Transcriptionally Controlled by the Interplay of cAMP-response Element-binding Protein and Its Binding Partner Inducible cAMP Early Repressor^*

Yinghui Hu^¶1, Ingrid V. Lund^||2, Maria C. Gravielle^**, David H. Farb^**, Amy R. Brooks-Kayal, and Shelley J. Russek³

From the Laboratory of Translational Epilepsy, Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts 02118 and ^¶Program in BioMedical Neuroscience, ^||Neuroscience Graduate Group, and ^**Laboratory of Molecular Neurobiology, Departments of Neurology and Pediatrics, University of Pennsylvania, Division of Neurology Children's Hospital, Philadelphia, Pennsylvania 19104

The regulated expression of type A -aminobutyric acid (GABA) receptor (GABA_AR) subunit genes plays a critical role in neuronal maturation and synaptogenesis. It is also associated with a variety of neurological diseases. Changes in GABA_A receptor 1 subunit gene (GABRA1) expression have been reported in animal models of epilepsy, alcohol abuse, withdrawal, and stress. Understanding the genetic mechanism behind such changes in subunit expression will lead to a better understanding of the role that signal transduction plays in control over GABA_AR function and brings with it the promise of providing new therapeutic tools for the prevention or cure of a variety of neurological disorders. Here we show that activation of protein kinase C increases 1 subunit levels via phosphorylation of CREB (pCREB) that is bound to the GABRA1 promoter (GABRA1p). In contrast, activation of protein kinase A decreases levels of 1 even in the presence of pCREB. Decrease of 1 is dependent upon the inducible cAMP early repressor (ICER) as directly demonstrated by ICER-induced down-regulation of endogenous 1-containing GABA_ARs at the cell surface of cortical neurons. Taken together with the fact that there are less 12-containing GABA_ARs in neurons after protein kinase A stimulation and that activation of endogenous dopamine receptors down-regulates 1 subunit mRNA levels subsequent to induction of ICER, our studies identify a transcriptional mechanism for regulating the cell surface expression of 1-containing GABA_ARs that is dependent upon the formation of CREB heterodimers.

Received for publication, June 21, 2007 , and in revised form, January 4, 2008.

^* This work was supported in part by National Institutes of Health Grants R01 NS051710 and R01 NS050393 and an American Epilepsy Society research initiative grant (to A. B. K. and S. J. R.). 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 Supported by a stipend from the BUSM Program in BioMedical Neuroscience.

² Supported by National Institutes of Health Grant F31 NS51943.

³ To whom correspondence should be addressed. Tel.: 617-638-4319; Fax: 617-639-4329; E-mail: srussek{at}bu.edu.

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