The mechanism of regaining responsiveness to ligands varies significantly from one GPCR to another. Certain internalized receptors are rapidly recycled to the plasma membrane in a fully resensitized state, whereas other GPCRs are slowly recycled or not recycled at all.41 In the case of the p2-adrenergic receptor, the dephosphory-lation of GRK-phosphorylated receptors in early endosomes seems critical for resen-sitization.42 The balance between protein kinase and protein phosphatase activities dictates the phosphorylation state and therefore has an effect on resensitization.

For instance, protein phosphatases 2A and 2B have been shown to dephospho-rylate the p2-adrenergic receptor.43 This receptor recruits p-arrestin to the plasma membrane when exposed to agonists, the receptor-arrestin complex dissociates, the p2-adrenergic receptor is internalized into clathrin-coated vesicles, rapidly dephos-phorylated, recycled, and resensitized within minutes. In contrast, the activated vasopressin V2 receptor is internalized with p-arrestin into endosomes, slowly dephosphorylated, recycled, and resensitized and the process takes hours.

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