Thyroid-stimulating hormone receptor activity after internalization.

The thyroid-stimulating hormone (TSH) receptor (TSHR) belongs to the large family of G-protein-coupled receptors (GPCRs) and is predominantly coupled to G(s). Thus, the effects of TSH are largely mediated by the stimulation of adenylyl cyclase and the ensuing rise of intracellular cyclic AMP (cAMP) concentrations. Like for other GPCRs, a prolonged stimulation of the TSHR leads to its internalization into endosomes followed by its recycling to the cell surface. Until recently, GPCRs were believed to activate "classical" G-protein-dependent pathways only when located on the cell surface and to cease doing so upon agonist-induced internalization. However, our recent findings on the TSHR and similar ones on the parathyroid hormone and sphingosine receptors suggest that internalized GPCRs can continue to signal through G(s)-cAMP in an intracellular compartment. Interestingly, this type of intracellular cAMP signaling differs from that occurring on the cell surface, as it is persistent and apparently leads to specific signaling outcomes. Although further studies are needed to investigate the possible physiological and pathophysiological consequences of GPCR-cAMP signaling in the endocytic compartment, endosomes should no longer be viewed as passive carriers for receptors en route to degradation but rather as specialized intracellular platforms for GPCR signaling.