Multiple motifs regulate the trafficking of GABA B receptors at distinct checkpoints within the secretory pathway

Abstract

γ-Aminobutyric acid type B receptors (GABA B) are G-protein-coupled receptors that mediate GABAergic inhibition in the brain. Their functional expression is dependent upon the formation of heterodimers between GABA BR1 and GABA BR2 subunits, a process that occurs within the endoplasmic reticulum (ER). However, the mechanisms that regulate receptor surface expression remain largely unknown. Here, we demonstrate that access to the cell surface for GABA BR1 is sequentially controlled by an RSR(R) motif and a LL motif within its cytoplasmic domain. In addition, we reveal that msec7-1, a guanine-nucleotide-exchange factor (GEF) for the ADP-ribosylation factor (ARF) family of GTPases, critical regulators of vesicular membrane trafficking, interacts with GABA BR1 via the LL motif in this subunit. Finally, we establish that msec7-1 modulates the cell surface expression of GABA B receptors, a process that is dependent upon the integrity of the LL motif in GABA BR1. Together, our results demonstrate that the cell surface expression of the GABA BR1 subunit is regulated by multiple motifs, which act at distinct checkpoints in the secretory pathway, and also suggest a novel role for msec7-1 in regulating the membrane trafficking of GABA BR1 subunits.