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J Biol Chem, Vol. 274, Issue 42, 29791-29795, October 15, 1999
From the Department of Cell Biology and Physiology, University of
New Mexico Health Science Center, Albuquerque, New Mexico 87131
Following activation by ligand, most G
protein-coupled receptors undergo rapid phosphorylation. This is
accompanied by a drastic decrease in the efficacy of continued or
repeated stimulation, due to receptor uncoupling from G protein and
receptor internalization. Such processing steps have been shown to be
absolutely dependent on receptor phosphorylation in the case of the
N-formyl peptide receptor (FPR). In this study, we report
results that indicate that the mechanisms responsible for
desensitization and internalization are distinct. Using site-directed
mutagenesis of the serine and threonine residues of the FPR carboxyl
terminus, we have characterized regions that differentially regulate
these two processes. Whereas substitution of all 11 Ser/Thr residues in
the carboxyl terminus prevents both desensitization and
internalization, substitution of four Ser/Thr residues between 328-332
blocks desensitization but has no effect on internalization. Similarly,
substitution of four Ser/Thr residues between positions 334 and 339 results in a deficit in desensitization but again no decrease in
internalization, suggesting that phosphorylation at either site evokes
receptor internalization, whereas maximal desensitization requires
phosphorylation at both sites. These results also indicate that
receptor internalization is not involved in the process of
desensitization. Further analysis of the residues between 328-332
revealed that restoration either of Ser328 and
Thr329 or of Thr331 and Ser332 was
sufficient to restore desensitization, suggesting that phosphorylation within either of these two sites, in addition to sites between residues
334 and 339, is sufficient to produce desensitization. Taken together,
these results indicate that the mechanisms involved in FPR processing
(uncoupling from G proteins and internalization) are regulated
differentially by phosphorylation at distinct sites within the carboxyl
terminus of the FPR. The relevance of this paradigm to other G
protein-coupled receptors is discussed.
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