The GABAB receptor interacts directly with the related transcription factors CREB2 and ATFx

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 97; no. 25; pp. 13967 - 13972
• Main Authors: White, J H, McIllhinney, R A, Wise, A, Ciruela, F, Chan, W Y, Emson, P C, Billinton, A, Marshall, F H
• Format: Journal Article
• Language: English
• Published: United States National Acad Sciences 05.12.2000; National Academy of Sciences; The National Academy of Sciences
• Subjects: Amino Acid Sequence; Animals; Baclofen - pharmacology; Biological Sciences; Brain; CHO Cells; Cricetinae; Cyclic AMP Response Element-Binding Protein; Humans; Molecular Sequence Data; Nerve Tissue Proteins - metabolism; Nervous system; Neurology; Precipitin Tests; Protein Binding; Proteins; Receptors, GABA-B - metabolism; Repressor Proteins; Subcellular Fractions - metabolism; Transcription Factors - metabolism; Transcriptional Activation - drug effects
• ISSN: 0027-8424; 1091-6490

γ-Aminobutyric acid type B (GABA B ) 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 GABA B receptor is made up of a heterodimer consisting of two subunits, GABA B -R1 and GABA B -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 GABA B -R1 and GABA B -R2 with two related transcription factors, CREB2 (ATF4) and ATFx. In primary neuronal cultures as well in recombinant Chinese hamster ovary cells expressing GABA B receptors, CREB2 is localized within the cytoplasm as well as the nucleus. Activation of the GABA B 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 GABA B receptor and CREB2, may play a role in long-term changes in the nervous system.