The metabotropic GABAB receptor directly interacts with the activating transcription factor 4.

2000 
G protein-coupled receptors regulate gene expression by cellular signaling cascades that target transcription factors and their recognition by specific DNA sequences. In the central nervous system, heteromeric metabotropic g-aminobutyric acid type B (GABAB) receptors through adenylyl cyclase regulate cAMP levels, which may control transcription factor binding to the cAMP response element. Using yeast-two hybrid screens of rat brain libraries, we now demonstrate that GABAB receptors are engaged in a direct and specific interaction with the activating transcription factor 4 (ATF-4), a member of the cAMP response element-binding protein /ATF family. As confirmed by pull-down assays, ATF-4 associates via its conserved basic leucine zipper domain with the C termini of both GABAB receptor (GABABR) 1 and GABABR2 at a site which serves to assemble these receptor subunits in heterodimeric complexes. Confocal fluorescence microscopy shows that GABABR and ATF-4 are strongly coclustered in the soma and at the dendritic membrane surface of both cultured hippocampal neurons as well as retinal amacrine cells in vivo .I n oocyte coexpression assays short term signaling of GABABRs via G proteins was only marginally affected by the presence of the transcription factor, but ATF-4 was moderately stimulated in response to receptor activation in in vivo reporter assays. Thus, inhibitory metabotropic GABABRs may regulate activity-dependent gene expression via a direct interaction with ATF-4. Many stimulatory neurotransmitters and hormones in the mammalian central nervous system have been found to cause long term changes in neuronal function, such as differentiation, plasticity, and learning (1‐ 4). These changes generally require agonist-driven activation of cellular signaling cascades, followed by the induction of transcriptional regulators that rec
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