Signaling by internalized G-protein-coupled receptors

G-protein-coupled receptors (GPCRs) are cell surface receptors and are generally assumed to signal to second messengers such as cyclic AMP (cAMP) exclusively from the plasma membrane. However, recent studies indicate that GPCRs can continue signaling to cAMP after internalization together with their agonists. Signaling from inside the cell is persistent and appears to trigger specific downstream effects. Here, we will review these recent data, which form the basis for a novel concept of intracellular GPCR signaling and suggest new and intriguing scenarios for the functions of GPCRs in the endocytic compartment. We propose that current models of GPCR signaling should be revised to accommodate the ability of receptors to change their signaling properties depending on their subcellular localization.

Introduction

Cells respond to environmental cues and communicate with each other through the activation of receptors located on the cell surface. G-protein-coupled receptors (GPCRs) form the largest family of such receptors. They mediate effects of neurotransmitters, hormones, ions, odorants and light. Their signals are essentially mediated via the activation of heterotrimeric G proteins and their effectors (e.g. adenylyl cyclase, phospholipase C, potassium and calcium channels). Because of their involvement in a large number of physiological and pathological processes, GPCRs have been subject to intensive investigation and represent major targets for current pharmacological intervention [1].

Similar to other classes of receptors, prolonged stimulation of GPCRs often leads to their internalization into endosomes, presumably via more than one internalization pathway 1, 2, 3. Although originally considered as a major mechanism of signal desensitization, the results of several studies performed over the past 15 years suggest other functions for receptor internalization [4], most notably receptor resensitization 1, 5, 6, 7 and signaling to the mitogen-activated protein kinase (MAPK) cascade [8]. In addition, proteolytic fragments of internalized Frizzled GPCRs have been shown to translocate to the nucleus where they might activate gene transcription [9]. In spite of these observations, it is generally believed that GPCR signaling to classical G-protein-dependent pathways, such as the G_s-dependent activation of adenylyl cyclase, occurs exclusively at the cell surface. This view has been challenged by three recent studies, which suggest that a previously unrecognized type of persistent GPCR signaling to cAMP can occur after ligand–receptor internalization 10, 11, 12. Here, we will review the evidence for the existence of GPCR–cAMP signaling pathways on endosomes, and their possible pathophysiological and pharmacological implications.