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The Journal of Neuroscience, July 7, 2004, 24(27):6115-6126; doi:10.1523/JNEUROSCI.1200-04.2004

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Cellular/Molecular
cAMP Response Element-Binding Protein, Activating Transcription Factor-4, and Upstream Stimulatory Factor Differentially Control Hippocampal GABA_BR1a and GABA_BR1b Subunit Gene Expression through Alternative Promoters

Janine L. Steiger, Sabita Bandyopadhyay, David H. Farb, ^* and Shelley J. Russek ^*

Laboratory of Molecular Neurobiology, Department of Pharmacology, Boston University School of Medicine, Boston, Massachusetts 02118

Expression of metabotropic GABA_B receptors is essential for slow inhibitory synaptic transmission in the CNS, and disruption of GABA_B receptor-mediated responses has been associated with several disorders, including neuropathic pain and epilepsy. The location of GABA_B receptors in neurons determines their specific role in synaptic transmission, and it is believed that sorting of subunit isoforms, GABA_BR1a and GABA_BR1b, to presynaptic or postsynaptic membranes helps to determine this role. GABA_BR1a and GABA_BR1b are thought to arise by alternative splicing of heteronuclear RNA. We now demonstrate that alternative promoters, rather than alternative splicing, produce GABA_BR1a and GABA_BR1b isoforms. Our data further show that subunit gene expression in hippocampal neurons is mediated by the cAMP response element-binding protein (CREB) by binding to unique cAMP response elements in the alternative promoter regions. Double-stranded oligonucleotide decoys selectively alter levels of endogenous GABA_BR1a and GABA_BR1b in primary hippocampal neurons, and CREB knock-out mice show changes in levels of GABA_BR1a and GABA_BR1b transcripts, consistent with decoy competition experiments. These results demonstrate a critical role of CREB in transcriptional mechanisms that control GABA_BR1 subunit levels in vivo. In addition, the CREB-related factor activating transcription factor-4 (ATF4) has been shown to interact directly with GABA_BR1 in neurons, and we show that ATF4 differentially regulates GABA_BR1a and GABA_BR1b promoter activity. These results, together with our finding that the depolarization-sensitive upstream stimulatory factor (USF) binds to a composite CREB/ATF4/USF regulatory element only in the absence of CREB binding, indicate that selective control of alternative GABA_BR1 promoters by CREB, ATF4, and USF may dynamically regulate expression of their gene products in the nervous system.

Key words: GABA_B receptor; transcription; CREB; ATF4; CREB2; USF

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Received March 31, 2004; revised May 19, 2004; accepted May 21, 2004.

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