Regulation of GPCR signal networks via membrane trafficking

Abstract

G-protein-coupled receptors (GPCRs) are a superfamily of cell surface signaling proteins that act as central molecular activators and integrators in all endocrine systems. Membrane trafficking of GPCRs is a fundamental process in shaping extensive signaling networks activated by these receptors. Mounting evidence has identified an increasingly complex network of pathways and protein interactions that a GPCR can traverse and associate with, indicating a multi-level system of regulation. This review will discuss the recent developments in how GPCRs are trafficked to the cell surface as newly synthesized receptors, their recruitment to the clathrin-mediated pathway for endocytosis, and their sorting to subsequent divergent post-endocytic fates, focusing primarily on hormone-activated GPCRs. Current models depicting the classic roles membrane trafficking plays in GPCR signaling have evolved to a highly regulated and complex system than previously appreciated. These developments impart key mechanistic information on how spatial and temporal aspects of GPCR signaling may be integrated and could provide pathway-specific targets to be exploited for therapeutic intervention.

Allosteric Modulation of M1 Muscarinic Acetylcholine Receptor Internalization and Subcellular Trafficking

“…Once internalized, receptors can be directed to degradative pathways (receptor down-regulation) or recycled back to the cell surface (37). Receptor trafficking through the endocytic machinery as well as the fate of internalized receptors is agonist-dependent (38 -40).…”

Estrogen Signaling in the Adrenal Cortex

“…[95][96][97] This trafficking forms the basis for GPER-1 desensitization (through endocytosis), resensitization (through recycling to plasma membrane), and down-regulation (through proteolytic degradation). 98,99 On interaction with its ligand(s), GPER-1 undergoes conformational changes that result in the dissociation of Gα from Gβγ subunit, leading to the intracellular activation of phosphoinositide-3-kinase, with ensuing increase of cAMP and intracellular Ca 2+ . 95,100 The latter increases mitochondrial Ca 2+ , resulting in Ca 2+ -dependent mitochondrial cAMP production and enhanced aldosterone secretion.…”

Regulation of G protein-coupled receptor trafficking and signaling by Rab GTPases

“…One major mechanism of spatiotemporal signal organization includes protein intracellular trafficking. 2 In addition to contributing to the rapid and effective desensitization of GPCR signaling, the endocytosis and intracellular trafficking of GPCRs can spatially and temporally determine G protein-dependent and -independent signaling pathways. Membrane trafficking may also provide novel compartments for signal transduction.…”