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Papers In Press, published online ahead of print January 13, 2003
Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232
Corresponding Author: Vsevolod.Gurevich{at}mcmail.vanderbilt.edu
The vast majority of G protein-coupled receptors (GPCRs) are desensitized by a uniform two-step mechanism: phosphorylation of an active receptor followed by arrestin binding. The arrestin-receptor complex is then internalized. Internalized receptor can be recycled back to the plasma membrane (resensitization) or targeted to lysosomes for degradation (down-regulation). The intracellular compartment where this choice is made and the molecular mechanisms involved are largely unknown. Here we used two arrestin2 mutants that bind with high affinity to phosphorylated and unphosphorylated agonist-activated b2-adrenergic receptor (b2AR) to manipulate the receptor-arrestin interface. We found that mutants support rapid internalization of b2AR similar to wild type arrestin2. At the same time, phosphorylation-independent arrestin2 mutants facilitate receptor recycling and sharply reduce the rate of receptor loss, effectively protecting b2AR from down-regulation even after very long (up to 24h) agonist exposure. Phosphorylation-independent arrestin2 mutants dramatically reduce receptor phosphorylation in response to an agonist both in vitro and in cells. Interestingly, co-expression of high levels of b-adrenergic receptor kinase (GRK2) restores receptor down-regulation in the presence of mutants to the levels observed with wild type arrestin2. Our data suggest that unphosphorylated receptor internalized in complex with mutant arrestins recycles faster than phosphoreceptor and is less likely to get degraded. Thus, targeted manipulation of the characteristics of an arrestin protein that binds to a GPCR can dramatically change receptor trafficking and its ultimate fate in a cell.
J. Biol. Chem, 10.1074/jbc.M209532200
Submitted on September 17, 2002
Revised on January 6, 2003
Accepted on January 13, 2003
The nature of the arrestin-receptor complex determines the ultimate fate of the internalized receptor
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