Abstract
G protein-coupled receptors (GPCRs) are the largest family of plasma
membrane receptors. They mediate the effects of several endogenous
cues and serve as important pharmacological targets. Although many
biochemical events involved in GPCR signaling have been characterized
in great detail, little is known about their spatiotemporal dynamics
in living cells. The recent advent of optical methods based on fluorescent
resonance energy transfer allows, for the first time, to directly
monitor GPCR signaling in living cells. Utilizing these methods,
it has been recently possible to show that the receptors for two
protein/peptide hormones, the TSH and the parathyroid hormone, continue
signaling to cAMP after their internalization into endosomes. This
type of intracellular signaling is persistent and apparently triggers
specific cellular outcomes. Here, we review these recent data and
explain the optical methods used for such studies. Based on these
findings, we propose a revision of the current model of the GPCR-cAMP
signaling pathway to accommodate receptor signaling at endosomes.
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