Hetero-oligomerization between GABAA and GABAB Receptors Regulates GABAB Receptor Trafficking

Abstract

The neurotransmitter γ-aminobutyric acid (GABA) mediates inhibitory signaling in the brain via stimulation of both GABAA receptors (GABA AR), which are chloride-permeant ion channels, and GABAB receptors (GABABR), which signal through coupling to G proteins. Here we report physical interactions between these two different classes of GABA receptor. Association of the GABAB receptor 1 (GABABR1) with the GABAA receptor γ2S subunit robustly promotes cell surface expression of GABABR1 in the absence of GABABR2, a closely related GABAB receptor that is usually required for efficient trafficking of GABABR1 to the cell surface. The GABABR1/γ2S complex is not detectably functional when expressed alone, as assessed in both ERK activation assays and physiological analyses in oocytes. However, the γ2S subunit associates not only with GABABR1 alone but also with the functional GABABR1/GABABR2 heterodimer to markedly enhance GABAB receptor internalization in response to agonist stimulation. These findings reveal that the GABABR1/γ2S interaction results in the regulation of multiple aspects of GABAB receptor trafficking, allowing for cross-talk between these two distinct classes of GABA receptor.