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PMID:10924501

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Citation

Nehring, RB, Horikawa, HP, El Far, O, Kneussel, M, Brandstätter, JH, Stamm, S, Wischmeyer, E, Betz, H and Karschin, A (2000) The metabotropic GABAB receptor directly interacts with the activating transcription factor 4. J. Biol. Chem. 275:35185-91

Abstract

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 gamma-aminobutyric acid type B (GABA(B)) 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 GABA(B) 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 GABA(B) receptor (GABA(B)R) 1 and GABA(B)R2 at a site which serves to assemble these receptor subunits in heterodimeric complexes. Confocal fluorescence microscopy shows that GABA(B)R 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. In oocyte coexpression assays short term signaling of GABA(B)Rs 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 GABA(B)Rs may regulate activity-dependent gene expression via a direct interaction with ATF-4.

Links

PubMed Online version:10.1074/jbc.M002727200

Keywords

Activating Transcription Factor 4; Amino Acid Sequence; Animals; Blotting, Western; Brain/metabolism; Cerebral Cortex/metabolism; Cloning, Molecular; Cyclic AMP/metabolism; DNA, Complementary/metabolism; Electrophoresis, Polyacrylamide Gel; Electrophysiology; Escherichia coli/metabolism; Gene Expression Regulation; Gene Library; Genes, Reporter; Glutathione Transferase/metabolism; Immunohistochemistry; Luciferases/metabolism; Models, Genetic; Molecular Sequence Data; Neurons/metabolism; Oocytes/metabolism; Protein Binding; Rats; Receptors, GABA-B/metabolism; Recombinant Fusion Proteins/metabolism; Retina/metabolism; Semliki forest virus/genetics; Sequence Homology, Amino Acid; Signal Transduction; Transcription Factors/metabolism; Transcription, Genetic; Two-Hybrid System Techniques; Xenopus laevis

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

RAT:ATF4

located_in

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

RAT:ATF4

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

RAT:ATF4

located_in

GO:0032590: dendrite membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

RAT:ATF4

involved_in

GO:0007214: gamma-aminobutyric acid signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:ATF4

involved_in

GO:0043267: negative regulation of potassium ion transport

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:ATF4

enables

GO:0008022: protein C-terminus binding

ECO:0000353: physical interaction evidence used in manual assertion

RGD:621537

F

Seeded From UniProt

complete

RAT:GABR1

enables

GO:0008134: transcription factor binding

ECO:0000353: physical interaction evidence used in manual assertion

RGD:621863

F

Seeded From UniProt

complete


See also

References

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