When trafficking and signaling mix: How subcellular location shapes G protein-coupled receptor activation of heterotrimeric G proteins

Abstract

G protein-coupled receptors (GPCRs) physically connect extracellular information with intracellular signal propagation. Membrane trafficking plays a supportive role by "bookending" signaling events: movement through the secretory pathway delivers GPCRs to the cell surface where receptors can sample the extracellular environment, while endocytosis and endolysosomal membrane trafficking provide a versatile system to titrate cellular signaling potential and maintain homeostatic control. Recent evidence suggests that, in addition to these important effects, GPCR trafficking actively shapes the cellular signaling response by altering the location and timing of specific receptor-mediated signaling reactions. Here, we review key experimental evidence underlying this expanding view, focused on GPCR signaling mediated through activation of heterotrimeric G proteins located in the cytoplasm. We then discuss lingering and emerging questions regarding the interface between GPCR signaling and trafficking.

Keywords: G protein; GPCR; endosome; signaling; trafficking.

FIGURE 1

“Layers” in the GPCR trafficking/signaling relationship. Layer 1 (left side): Membrane trafficking processes “bookend” receptor signaling by trimeric G proteins from the plasma membrane (step 2), using biosynthetic (step 1) and endocytic (step 3) transport to modulate the number of functional surface receptors. Layer 2 (right side): Additional signaling can be initiated by receptor coupling to cytoplasmic G proteins from intracellular membranes. We propose that these layers function together to determine the integrated cellular response