Multiple motifs regulate the trafficking of GABAB 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.