The GABAB receptor interacts directly with the related transcription factors CREB2 and ATFx
- Julia H. White*,†,
- R. A. Jeffrey McIllhinney‡,
- Alan Wise*,
- Francisco Ciruela‡,
- Wai-Yee Chan‡,
- Piers C. Emson§,
- Andrew Billinton§, and
- Fiona H. Marshall*
- *Receptor Systems, Molecular Pharmacology Department, Glaxo Wellcome Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, United Kingdom; ‡MRC Anatomical Neuropharmacology Unit, Mansfield Road, Oxford, OX1 3TH, United Kingdom; and §Department of Neurobiology, The Babraham Institute, Babraham, Cambridge, CB2 4AT, United Kingdom
-
Communicated by Michael J. Berridge, The Babraham Institute, Cambridge, United Kingdom (received for review June 30, 2000)
Abstract
γ-Aminobutyric acid type B (GABAB) receptors mediate the metabotropic actions of the inhibitory neurotransmitter GABA. These seven-transmembrane receptors are known to signal primarily through activation of G proteins to modulate the action of ion channels or second messengers. The functional GABAB receptor is made up of a heterodimer consisting of two subunits, GABAB-R1 and GABAB-R2, which interact via coiled-coil domains in their C-terminal tails. By using a yeast two-hybrid approach, we have identified direct interactions between the C-terminal tails of GABAB-R1 and GABAB-R2 with two related transcription factors, CREB2 (ATF4) and ATFx. In primary neuronal cultures as well in recombinant Chinese hamster ovary cells expressing GABAB receptors, CREB2 is localized within the cytoplasm as well as the nucleus. Activation of the GABAB receptor by the specific agonist baclofen leads to a marked translocation and accumulation of CREB2 from the cytoplasm into the nucleus. We demonstrate that receptor stimulation results in activation of transcription from a CREB2 responsive reporter gene. Such a signaling mechanism is unique among Family C G protein-coupled receptors and, in the case of the GABAB receptor and CREB2, may play a role in long-term changes in the nervous system.
Footnotes
-
↵ † To whom reprint requests should be addressed. E-mail: Jw6155{at}glaxowellcome.co.uk.
-
Data deposition: The sequence reported in this paper has been deposited in the GenBank database (accession no. AF305687).
-
Article published online before print: Proc. Natl. Acad. Sci. USA, 10.1073/pnas.240452197.
-
Article and publication date are at www.pnas.org/cgi/doi/10.1073/pnas.240452197
- Abbreviations:
- GABA,
- γ-aminobutyric acid;
- GPCR,
- G protein-coupled receptor;
- YTH,
- Yeast two-hybrid;
- CHO,
- Chinese hamster ovary;
- eGFP,
- enhanced green fluorescent protein;
- CAT,
- chloramphenicol acetyltransferase;
- MAPK,
- mitogen-activated protein kinase;
- PTX,
- pertussis toxin;
- bZIP,
- basic leucine zipper
- Copyright © 2000, The National Academy of Sciences
