Turning off the signal: Mechanisms that attenuate signaling by G protein-coupled receptors

Cellular responses to agonists of G protein-coupled receptors are rapidly attenuated. Mechanisms of signal attenuation include ligand removal from the extracellular fluid and receptor desensitization, endocytosis, and downregulation. Cell surface peptidases degrade neuropeptides in the extracellular fluid and thereby terminate their biological actions. G protein receptor kinases and second messenger kinases phosphorylate receptors, permit interaction with arrestins, and thus uncouple receptors from G proteins to mediate desensitization. Agonist-induced receptor endocytosis contributes to desensitization by depleting the cell surface of high-affinity receptors, while recycling of internalized receptors mediates resensitization of cellular responses. Receptor downregulation is a form of desensitization that occurs during continuous, long-term exposure of cells to receptor agonists. Downregulation is characterized by the depletion of the cellular receptor content due to alterations in the rate of receptor degradation and synthesis. These regulatory mechanisms are important, for they govern the ability of cells to respond to agonists.