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Science 2 February 2007:
Vol. 315. no. 5812, pp. 663 - 666
DOI: 10.1126/science.1134562
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Reports

Targeting of Diacylglycerol Degradation to M1 Muscarinic Receptors by ß-Arrestins

Christopher D. Nelson,1 Stephen J. Perry,2* Debra S. Regier,3 Stephen M. Prescott,3 Matthew K. Topham,3 Robert J. Lefkowitz2,4{dagger}

Seven-transmembrane receptor (7TMR) signaling is transduced by second messengers such as diacylglycerol (DAG) generated in response to the heterotrimeric guanine nucleotide–binding protein Gq and is terminated by receptor desensitization and degradation of the second messengers. We show that ß-arrestins coordinate both processes for the Gq-coupled M1 muscarinic receptor. ß-Arrestins physically interact with diacylglycerol kinases (DGKs), enzymes that degrade DAG. Moreover, ß-arrestins are essential for conversion of DAG to phosphatidic acid after agonist stimulation, and this activity requires recruitment of the ß-arrestin–DGK complex to activated 7TMRs. The dual function of ß-arrestins, limiting production of diacylglycerol (by receptor desensitization) while enhancing its rate of degradation, is analogous to their ability to recruit adenosine 3',5'-monophosphate phosphodiesterases to Gs-coupled ß2-adrenergic receptors. Thus, ß-arrestins can serve similar regulatory functions for disparate classes of 7TMRs through structurally dissimilar enzymes that degrade chemically distinct second messengers.

1 Department of Biochemistry, Duke University Medical Center, Durham, NC 27710, USA.
2 Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA.
3 Huntsman Cancer Institute and Department of Internal Medicine, University of Utah, Salt Lake City, UT 84112, USA.
4 Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.

* Present address: Neurocrine Biosciences Inc., 12790 El Camino Real, San Diego, CA 92130, USA.

{dagger} To whom correspondence should be addressed. E-mail: lefko001{at}receptor-biol.duke.edu.

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