Subtype-selective Interaction with the Transcription Factor CCAAT/Enhancer-binding Protein (C/EBP) Homologous Protein (CHOP) Regulates Cell Surface Expression of GABAB Receptors

Abstract The metabotropic γ-aminobutyric acid, type B (GABAB) receptors mediate the slow component of GABAergic transmission in the brain. Functional GABAB receptors are heterodimers of the two subunits GABAB1 and GABAB2, of which GABAB1 exists in two main isoforms, GABAB1a and GABAB1b. The significance of the structural heterogeneity of GABAB receptors, the mechanism leading to their differential targeting in neurons as well as the regulation of cell surface numbers of GABAB receptors, is poorly understood. To gain insights into these processes, we searched for proteins interacting with the C-terminal domain of GABAB2. Here, we showed that the transcription factor CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) directly interacts with GABAB receptors in a subtype-selective manner to regulate cell surface expression of GABAB1a/GABAB2 receptors upon co-expression in HEK 293 cells. The interaction of CHOP with GABAB1a/GABAB2 receptors resulted in their intracellular accumulation and in a reduced number of cell surface receptors. This regulation required the interaction of CHOP via two distinct domains with the heterodimeric receptor; its C-terminal leucine zipper associates with the leucine zipper present in the C-terminal domain of GABAB2, and its N-terminal domain associates with an as yet unidentified site on GABAB1a. In conclusion, the data indicated a subtype-selective regulation of cell surface receptors by interaction with the transcription factor CHOP.