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.
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