G protein-coupled receptor internalization

Definition

Target type: biologicalprocess

The process that results in the uptake of a G protein-coupled receptor into an endocytic vesicle. [PMID:8396717]

G protein-coupled receptors (GPCRs) are integral membrane proteins that mediate cellular responses to a wide range of extracellular signals, including hormones, neurotransmitters, and light. Upon ligand binding, GPCRs undergo a complex series of conformational changes that trigger downstream signaling pathways. Internalization, a process by which GPCRs are removed from the cell surface, is a key regulatory mechanism that modulates GPCR signaling and prevents excessive activation.

GPCR internalization typically occurs through clathrin-mediated endocytosis, a process that involves the formation of clathrin-coated pits on the plasma membrane. These pits invaginate and pinch off to form clathrin-coated vesicles that encapsulate the internalized GPCR.

The internalization process can be triggered by various mechanisms, including:

- **Ligand binding:** Most GPCRs are internalized upon ligand binding, although the kinetics and efficiency of internalization can vary depending on the specific receptor and ligand.
- **Agonist-induced phosphorylation:** Ligand binding often leads to phosphorylation of the GPCR by kinases, such as G protein-coupled receptor kinases (GRKs). Phosphorylation creates binding sites for adaptor proteins, such as β-arrestin, which facilitate the recruitment of clathrin and other proteins involved in endocytosis.
- **Constitutive internalization:** Some GPCRs undergo internalization even in the absence of ligand binding. This constitutive internalization can serve as a regulatory mechanism to control receptor levels at the cell surface.

Once internalized, GPCRs can follow different fates:

- **Recycling:** Many GPCRs are recycled back to the cell surface, allowing them to respond to subsequent ligand stimulation. This recycling process often involves the removal of the phosphorylation sites and the dissociation of β-arrestin.
- **Degradation:** Some GPCRs are targeted for degradation in lysosomes, where they are broken down into their constituent amino acids. This degradation pathway can serve to downregulate GPCR signaling and prevent excessive receptor activation.
- **Translocation to other cellular compartments:** In some cases, internalized GPCRs can be translocated to other cellular compartments, such as the nucleus, where they may participate in non-canonical signaling pathways.

The internalization and trafficking of GPCRs are tightly regulated processes that are crucial for maintaining appropriate cellular responses to external signals. Dysregulation of GPCR internalization can contribute to various diseases, including cancer, neurodegenerative disorders, and metabolic diseases. Therefore, understanding the molecular mechanisms underlying GPCR internalization is essential for developing new therapeutic strategies for treating these disorders.'
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Proteins (5)

Compounds (495)