The GABA(B) receptor interacts directly with the related transcription factors CREB2 and ATFx

gamma -Aminobutyric acid type B (GABA(B)) receptors mediate the metabotropi c actions of the inhibitory neurotransmitter GABA. These seven-transmembran e 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, G ABA(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 d irect interactions between the C-terminal tails of GABA(B)-R1 and GABA(B)-R 2 with two related transcription factors, CREB2 (ATF4) and ATFx. In primary neuronal cultures as well in recombinant Chinese hamster ovary cells expre ssing GABA(B) receptors, CREB2 is localized within the cytoplasm as well as the nucleus. Activation of the GABAB receptor by the specific agonist bacl ofen leads to a marked translocation and accumulation of CREB2 from the cyt oplasm into the nucleus. We demonstrate that receptor stimulation results i n activation of transcription from a CREB2 responsive reporter gene. Such a signaling mechanism is unique among Family C C protein-coupled receptors a nd, in the case of the GABA(B) receptor and CREB2, may play a role in long- term changes in the nervous system.