Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

Science 315 (5812): 663-666

Copyright © 2007 by the American Association for the Advancement of Science

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}

Abstract: 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.


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
The Role of Diacylglycerol Kinase {zeta} and Phosphatidic Acid in the Mechanical Activation of Mammalian Target of Rapamycin (mTOR) Signaling and Skeletal Muscle Hypertrophy.
J.-S. You, H. C. Lincoln, C.-R. Kim, J. W. Frey, C. A. Goodman, X.-P. Zhong, and T. A. Hornberger (2014)
J. Biol. Chem. 289, 1551-1563
   Abstract »    Full Text »    PDF »
Noncanonical Control of Vasopressin Receptor Type 2 Signaling by Retromer and Arrestin.
T. N. Feinstein, N. Yui, M. J. Webber, V. L. Wehbi, H. P. Stevenson, J. D. King Jr., K. R. Hallows, D. Brown, R. Bouley, and J.-P. Vilardaga (2013)
J. Biol. Chem. 288, 27849-27860
   Abstract »    Full Text »    PDF »
Diacylglycerol Kinase {delta} Modulates Akt Phosphorylation through Pleckstrin Homology Domain Leucine-rich Repeat Protein Phosphatase 2 (PHLPP2).
T. M. Crotty, T. Nakano, D. M. Stafforini, and M. K. Topham (2013)
J. Biol. Chem. 288, 1439-1447
   Abstract »    Full Text »    PDF »
Diacylglycerol kinase {zeta} controls diacylglycerol metabolism at the immunological synapse.
S. I. Gharbi, E. Rincon, A. Avila-Flores, P. Torres-Ayuso, M. Almena, M. A. Cobos, J. P. Albar, and I. Merida (2011)
Mol. Biol. Cell 22, 4406-4414
   Abstract »    Full Text »    PDF »
Beyond Desensitization: Physiological Relevance of Arrestin-Dependent Signaling.
L. M. Luttrell, D. Gesty-Palmer, and D. R. Sibley (2010)
Pharmacol. Rev. 62, 305-330
   Abstract »    Full Text »    PDF »
Cross Talk between Phosphatidylinositol 3-Kinase and Cyclic AMP (cAMP)-Protein Kinase A Signaling Pathways at the Level of a Protein Kinase B/{beta}-Arrestin/cAMP Phosphodiesterase 4 Complex.
E. Bjorgo, S. A. Solheim, H. Abrahamsen, G. S. Baillie, K. M. Brown, T. Berge, K. Okkenhaug, M. D. Houslay, and K. Tasken (2010)
Mol. Cell. Biol. 30, 1660-1672
   Abstract »    Full Text »    PDF »
Selective activation of the M1 muscarinic acetylcholine receptor achieved by allosteric potentiation.
L. Ma, M. A. Seager, M. Wittmann, M. Jacobson, D. Bickel, M. Burno, K. Jones, V. K. Graufelds, G. Xu, M. Pearson, et al. (2009)
PNAS 106, 15950-15955
   Abstract »    Full Text »    PDF »
Selective engagement of G protein coupled receptor kinases (GRKs) encodes distinct functions of biased ligands.
D. A. Zidar, J. D. Violin, E. J. Whalen, and R. J. Lefkowitz (2009)
PNAS 106, 9649-9654
   Abstract »    Full Text »    PDF »
Clathrin Regulates the Association of PIPKI{gamma}661 with the AP-2 Adaptor {beta}2 Appendage.
J. R. Thieman, S. K. Mishra, K. Ling, B. Doray, R. A. Anderson, and L. M. Traub (2009)
J. Biol. Chem. 284, 13924-13939
   Abstract »    Full Text »    PDF »
Synaptic removal of diacylglycerol by DGK{zeta} and PSD-95 regulates dendritic spine maintenance.
K. Kim, J. Yang, X.-P. Zhong, M.-H. Kim, Y. S. Kim, H. W. Lee, S. Han, J. Choi, K. Han, J. Seo, et al. (2009)
EMBO J. 28, 1170-1179
   Abstract »    Full Text »    PDF »
An adrenal {beta}-arrestin 1-mediated signaling pathway underlies angiotensin II-induced aldosterone production in vitro and in vivo.
A. Lymperopoulos, G. Rengo, C. Zincarelli, J. Kim, S. Soltys, and W. J. Koch (2009)
PNAS 106, 5825-5830
   Abstract »    Full Text »    PDF »
M3 Muscarinic Acetylcholine Receptor-Mediated Signaling Is Regulated by Distinct Mechanisms.
J. Luo, J. M. Busillo, and J. L. Benovic (2008)
Mol. Pharmacol. 74, 338-347
   Abstract »    Full Text »    PDF »
{beta}-Arrestin Scaffolding of Phosphatidylinositol 4-Phosphate 5-Kinase I{alpha} Promotes Agonist-stimulated Sequestration of the {beta}2-Adrenergic Receptor.
C. D. Nelson, J. J. Kovacs, K. N. Nobles, E. J. Whalen, and R. J. Lefkowitz (2008)
J. Biol. Chem. 283, 21093-21101
   Abstract »    Full Text »    PDF »
Dynamics of Somatostatin Type 2A Receptor Cargoes in Living Hippocampal Neurons.
B. Lelouvier, G. Tamagno, A. M. Kaindl, A. Roland, V. Lelievre, V. Le Verche, C. Loudes, P. Gressens, A. Faivre-Baumann, Z. Lenkei, et al. (2008)
J. Neurosci. 28, 4336-4349
   Abstract »    Full Text »    PDF »
{beta}-Arrestins: Multifunctional Cellular Mediators.
L. Barki-Harrington and H. A. Rockman (2008)
Physiology 23, 17-22
   Abstract »    Full Text »    PDF »
Role of the Diacylglycerol Kinase {alpha}-Conserved Domains in Membrane Targeting in Intact T Cells.
E. Merino, M. A. Sanjuan, I. Moraga, A. Cipres, and I. Merida (2007)
J. Biol. Chem. 282, 35396-35404
   Abstract »    Full Text »    PDF »
Functional specialization of beta-arrestin interactions revealed by proteomic analysis.
K. Xiao, D. B. McClatchy, A. K. Shukla, Y. Zhao, M. Chen, S. K. Shenoy, J. R. Yates III, and R. J. Lefkowitz (2007)
PNAS 104, 12011-12016
   Abstract »    Full Text »    PDF »
Highlights From The Literature.
(2007)
Physiology 22, 158-160
   Full Text »    PDF »
CELL SIGNALING: β-Arrestin, a Two-fisted Terminator.
E. F. Grady (2007)
Science 315, 605-606
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882