Targeting of diacylglycerol degradation to M1 muscarinic receptors by beta-arrestins.
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 beta-arrestins coordinate both processes for the Gq-coupled M1 muscarinic receptor. beta-Arrestins physically interact with diacylglycerol kinases (DGKs), enzymes that degrade DAG. Moreover, beta-arrestins are essential for conversion of DAG to phosphatidic acid after agonist stimulation, and this activity requires recruitment of the beta-arrestin-DGK complex to activated 7TMRs. The dual function of beta-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 beta2-adrenergic receptors. Thus, beta-arrestins can serve similar regulatory functions for disparate classes of 7TMRs through structurally dissimilar enzymes that degrade chemically distinct second messengers.
Nelson
Christopher D
CD
Department of Biochemistry, Duke University Medical Center, Durham, NC 27710, USA.
Perry
Stephen J
SJ
Regier
Debra S
DS
Prescott
Stephen M
SM
Topham
Matthew K
MK
Lefkowitz
Robert J
RJ
D000818:Animals; D019390:Arrestins / Q000378:metabolism*; D019556:COS Cells; D002217:Carbachol / Q000494:pharmacology; D002460:Cell Line; D002522:Chlorocebus aethiops; D019852:Diacylglycerol Kinase / Q000235:genetics / Q000378:metabolism*; D004075:Diglycerides / Q000378:metabolism*; D006801:Humans; D009154:Mutation; D010712:Phosphatidic Acids / Q000378:metabolism; D011485:Protein Binding; D034741:RNA, Small Interfering; D043643:Receptor, Muscarinic M1 / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015290:Second Messenger Systems; D015398:Signal Transduction; D014162:Transfection; D000071557:beta-Arrestins
D019390:Arrestins; D004075:Diglycerides; D010712:Phosphatidic Acids; D034741:RNA, Small Interfering; D043643:Receptor, Muscarinic M1; D011993:Recombinant Fusion Proteins; D000071557:beta-Arrestins; D002217:Carbachol; D019852:Diacylglycerol Kinase