GPCRarrestin

GPCRarrestin refers to the interaction between G protein-coupled receptors (GPCRs) and arrestin proteins, a critical regulatory mechanism in cellular signaling pathways. GPCRs are a large family of membrane proteins that transduce extracellular signals—such as hormones, neurotransmitters, and light—to intracellular responses. Upon activation by their ligands, GPCRs initially stimulate G proteins to propagate signals, but prolonged or excessive stimulation can lead to desensitization, a process where the receptor becomes less responsive.

Arrestins are cytosolic adaptor proteins that play a pivotal role in this desensitization. There are four known arrestin isoforms in mammals: arrestin-1 (visual arrestin), arrestin-2 (β-arrestin 1), arrestin-3 (β-arrestin 2), and arrestin-4 (cone arrestin). Upon receptor activation, arrestins bind to phosphorylated serine or threonine residues on the intracellular tail of the GPCR, inducing a conformational change that uncouples the receptor from G proteins. This prevents further G protein-mediated signaling, effectively terminating the response.

Beyond desensitization, arrestin binding also facilitates receptor internalization through clathrin-mediated endocytosis, directing the receptor to lysosomes for degradation or recycling back to the cell surface. Additionally, arrestins can act as scaffolds, recruiting signaling molecules such as c-Src kinases, β-arrestin–associated C-kinase substrates (BARCs), and G protein-coupled receptor kinases (GRKs) to form signaling complexes. These complexes can initiate alternative signaling pathways independent of G proteins, contributing to diverse cellular outcomes, including gene expression, cell migration, and proliferation.

The GPCR-arrestin interaction is dynamically regulated, with dephosphorylation of the receptor and arrestin dissociation allowing for receptor resensitization and reuse. Dysregulation of this process has been implicated in various diseases, including cardiovascular disorders, cancer, and neurological conditions, making it a target for therapeutic intervention. Understanding the molecular intricacies of GPCR-arrestin signaling continues to be an active area of research with implications for drug discovery.