desensitization of G protein-coupled receptor signaling pathway

Definition

Target type: biologicalprocess

The process that stops, prevents, or reduces the frequency, rate or extent of G protein-coupled receptor signaling pathway after prolonged stimulation with an agonist of the pathway. [PMID:8396717]

G protein-coupled receptor (GPCR) desensitization is a crucial regulatory mechanism that fine-tunes cellular responses to prolonged or excessive stimulation. It involves a cascade of events that dampen the signaling output of GPCRs, preventing overactivation and maintaining cellular homeostasis. The process can be broadly divided into three major steps: receptor phosphorylation, receptor sequestration, and downregulation.

1. **Receptor phosphorylation:** The initial step in desensitization involves the phosphorylation of the activated GPCR by specific kinases, primarily G protein-coupled receptor kinases (GRKs). GRKs are a family of serine/threonine kinases that specifically target activated GPCRs. Upon receptor activation, GRKs are recruited to the plasma membrane, where they phosphorylate specific serine and threonine residues in the C-terminal tail and intracellular loops of the receptor. This phosphorylation event creates binding sites for a family of proteins called arrestins.

2. **Arrestin binding and receptor sequestration:** Arrestins are adaptor proteins that bind to phosphorylated GPCRs. Arrestin binding has several important consequences. First, it physically blocks the interaction of the receptor with its cognate G protein, effectively uncoupling the receptor from downstream signaling pathways. Second, arrestins act as molecular scaffolds, recruiting other proteins to the receptor complex, including clathrin and adaptor protein 2 (AP-2), which mediate endocytosis. This process, known as receptor sequestration, leads to the internalization of the receptor from the plasma membrane into intracellular compartments.

3. **Downregulation:** Once internalized, the receptor can be either recycled back to the plasma membrane or targeted for degradation. Recycling allows for the re-expression of the receptor at the cell surface, restoring signaling capacity. Alternatively, the internalized receptor can be trafficked to lysosomes, where it is degraded. This process, known as downregulation, leads to a reduction in the overall number of receptors at the cell surface, further attenuating signaling.

In summary, GPCR desensitization is a multi-step process that involves receptor phosphorylation, arrestin binding, receptor sequestration, and downregulation. These events work in concert to fine-tune cellular responses to GPCR activation, preventing overstimulation and maintaining cellular homeostasis. The desensitization process is a complex and highly regulated event, with various factors influencing its kinetics and extent. The specific mechanisms and components involved in desensitization can vary depending on the type of GPCR and the cellular context.'
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Proteins (5)

Compounds (280)