GABA(B) receptors couple directly to the transcription factor ATF4

The inhibitory neurotransmitter gamma -aminobutyric acid (GABA), acts at io notropic (GABA(A) and GABA(C)) and metabotropic (GABA(B)) receptors. Functi onal GABA(B) receptors are heterodimers of GABA(B(1)) and GABA(B(2)) subuni ts. Here we show a robust, direct, and specific interaction between the coi led-coil domain present in the C-terminus of the GABA(B(1)) subunit and the transcription factor ATF4 (also known as CREB2). ATF4 and GABA(B(2)) bindi ng to the GABA(B(1)) subunit were mutually exclusive. In rat hippocampal ne urons native GABA(B(1)) showed surprisingly little similarity to GABA(B(2)) in its subcellular distribution, GABA(B(1)) and ATF4 however, were highly colocalized throughout the cell and displayed a punctate distribution withi n the dendrites. Activation of GABA(B) receptors in hippocampal neurons cau sed a dramatic translocation of ATF4 out of the nucleus into the cytoplasm, These data suggest a novel neuronal signaling pathway that could regulate the functional expression of GABA(B) receptors and/or modulate gene transcr iption.