Classical and new roles of beta-arrestins in the regulation of G-protein-coupled receptors

In the classical model of G-protein-coupled receptor (GPCR) regulation, arr estins terminate receptor signalling. After receptor activation, arrestins desensitize phosphorylated GPCRs, blocking further activation and initiatin g receptor Internalization. This function of arrestins is exemplified by st udies on the role of arrestins in the development of tolerance to, but not dependence on, morphine. Arrestins also link GPCRs to several signalling pa thways, including activation of the non-receptor tyrosine kinase SRC and mi togen-activated protein kinase. In these cascades, arrestins function as ad aptors and scaffolds, bringing sequentially acting kinases into proximity w ith each other and the receptor, The signalling roles of arrestins have bee n expanded even further with the discovery that the formation of stable rec eptor-arrestin complexes Initiates photoreceptor apoptosis in Drosophila, l eading to retinal degeneration. Here we review our current understanding of arrestin function, discussing both its classical and newly discovered role s.