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G protein-coupled receptor (GPCR) signaling plays a crucial role in cell functioning. GPCR desensitization is an equally essential process. It allows cells to respond to changing environments and regain sensitivity to new stimuli while preventing unnecessary stimulation when no longer needed. Prolonged exposure to stimuli leads to GPCR desensitization. It involves blocking the receptors from binding and activating additional G proteins. This inhibits activation of downstream effectors, thereby ensuring no further response.

GPCRs are inactivated by feedback repression, where an end product of a pathway blocks upstream signaling proteins such as the receptor. One such end product is protein kinase A (PKA). It phosphorylates serine and threonine residues at the cytosolic domain of the GPCR. The phosphorylated receptor cannot effectively bind and activate additional G proteins, thereby switching off signaling.

The binding of epinephrine to β-adrenergic receptors or glucagon to glucagon receptors activates Gɑs. Gɑs further stimulate PKA as the downstream effector protein in response to the binding of either ligand to their respective GPCRs. Prolonged exposure to epinephrine enhances PKA activity. PKA phosphorylates and represses its β-adrenergic receptors. However, they also desensitize other Gɑs coupled receptors, such as the glucagon receptors, even though they are not stimulated by epinephrine. This cross-regulation is called heterologous desensitization.

In other cases, the serine and threonine kinases termed G protein-coupled receptor kinases(GRKs) phosphorylate and inhibit specific ligand-bound GPCRs. For example, β-adrenergic receptors are phosphorylated by a GRK termed β-adrenergic receptor kinase (BARK). This type of regulation is called homologous desensitization, where respective GRKs inactivate only a specific ligand-bound GPCR. Phosphorylation of GPCRs by GRK promotes β-arrestin binding that blocks receptors in three ways:

  • Receptor inactivation: β-arrestin protein competes and binds phosphorylated GPCRs, preventing additional G proteins' binding.
  • Receptor sequestration: β-arrestins can bind clathrin and adaptor protein and induce clathrin-mediated endocytosis of the phosphorylated receptors. This makes the receptors inaccessible to the extracellular ligands. Eventually, as the receptor gets dephosphorylated and returned to the plasma membrane, it initiates another round of signaling events.
  • Receptor downregulation: β-arrestin-bound receptors often are ubiquitinylated, and instead of recycling, the endocytosed receptors are degraded by lysosomes.
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