Signal Transduction (IND 447)

G Protein Coupled Receptor Desensitization and Downregulation

David J. Culp, Ph.D.

Brief Description:  Persistent exposure of receptors to an agonist can result in the eventual loss of receptor-activated function or desensitization.  Desensitization has been studied mostly with respect to receptor function and expression, although additional cellular events may occur more downstream in signal transduction pathways.  Desensitization is cell specific and dependent upon both the expression and subcellular localization of specific components that function in desensitization processes.   Three general mechanisms are associated with desensitization of G-protein coupled receptors: 1) receptor phosphorylation; 2) receptor internalization or sequestration; and 3) receptor downregulation.  Receptors are phosphorylated in an agonist-dependent manner that is correlated (both with respect to time and dose) with a decreased affinity of receptors for agonist, as well as attenuated receptor function.  G-protein coupled receptors are substrates for second messenger kinases (i.e.: protein kinase C) and members of the G-protein-coupled receptor kinases.  Phosphorylation by these two families of kinases occurs at different receptor sites that include carboxyl-terminal threonine residues.  Agonist-induced receptor phosphorylation by G-protein coupled receptor kinases increases the affinity of receptor binding to a arrestin molecule.  Arrestin-receptor binding prevents further signal transduction between receptor and G-proteins by steric mechanisms.

Another process associated with agonist-induced receptor desensitization is the temperature sensitive sequestration of cell-surface receptors.  Receptor activation can result in reversible sequestration of receptors into an intracellular membrane compartment which: 1) exhibits a density lower than plasma membranes; and 2) are inaccessible to hydrophilic antagonists, but still accessible to more hydrophobic antagonists.  Receptor-arrestin binding facilitates receptor sequestration.  Receptor sequestration may involve different membrane trafficking pathways involving either caveolae, clathrin-coated, or non-coated vesicles.  Sequestered receptors can either recycle to the cell-surface or enter the endolysosomal pathway and eventually be degraded.

Both receptor phosphorylation and sequestration are associated primarily with more rapid receptor desensitization, which occurs over a period of only a few minutes.  With more persistent exposure to agonist, a slower phase (typically hours) of receptor downregulation occurs in which the steady-state level of receptor protein is decreased.  Mechanisms responsible for the agonist-induced reduction in the cellular density of receptors (homologous receptor downregulation) remain largely unclear but involve appropriate changes in either receptor synthesis (i.e.: reduction in the steady state level of receptor mRNA) and/or receptor degradation.  Receptor downregulation is also cell specific and involves the complex interaction between multiple cellular events to influence receptor expression.

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