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

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.