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J. Biol. Chem., Vol. 279, Issue 23, 24578-24584, June 4, 2004

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Arrestins Block G Protein-coupled Receptor-mediated Apoptosis^*

Chetana M. Revankar, Charlotte M. Vines, Daniel F. Cimino, and Eric R. Prossnitz¶

From the Department of Cell Biology & Physiology and University of New Mexico Cancer Research and Treatment Center, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131

G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptors (GPCRs) activate numerous cellular signals through the combined actions of G proteins, GPCR kinases, and arrestins. Although arrestins have traditionally been thought of as mediating GPCR desensitization, they have now been shown to play important roles in the internalization, trafficking, and signaling of many GPCRs. We demonstrate that in cells devoid of arrestins, the stimulation of numerous GPCRs including the N-formyl peptide receptor (FPR) initiates rapid cell rounding, annexin V positivity, and caspase activation followed by cell death. The apoptotic response is initiated by G protein signaling and involves activation of phosphoinositide 3-kinase, mitogen-activated protein kinases, and c-Src resulting in cytochrome c release from mitochondria and ultimately caspase 9 and caspase 3 activation. Reconstitution with either arrestin-2 or arrestin-3 is completely sufficient to prevent FPR-mediated apoptosis. Surprisingly, a non-desensitizing and non-internalizing mutant of the FPR is unable to initiate apoptosis, indicating that receptor phosphorylation and internalization, but not solely chronic activation due to a lack of desensitization, are critical determinants for the induction of apoptosis by the FPR. We further demonstrate that this response is not unique to the FPR with numerous additional GPCRs, including the V2 vasopressin, angiotensin II (type 1A), and CXCR2 receptors, capable of initiating apoptosis upon stimulation, whereas GPCRs such as the ₂-adrenergic receptor and CXCR4 are not capable of initiating apoptotic signaling. These data demonstrate for the first time that arrestins play a critical and completely unexpected role in the suppression GPCR-mediated apoptosis, which we show is a common consequence of GPCR-mediated cellular activation in the absence of arrestins.

Received for publication, February 26, 2004 , and in revised form, March 16, 2004.

^* This work was supported in part by National Institutes of Health Grants AI36357 and AI43932 and the University of New Mexico Cancer Research and Treatment Center (to E. R. P.). Flow cytometry data and confocal microscopy images in this paper were generated in the Flow Cytometry and Fluorescence Microscopy Facilities, respectively, at the University of New Mexico Health Sciences Center, which received support from National Center for Research Resources (NCRR) 1 S10 RR14668, NSF MCB9982161, NCRR P20 RR11830, and NCI R24 CA88339, National Institutes of Health, the University of New Mexico Health Sciences Center, and the University of New Mexico Cancer Research and Treatment Center. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this work.

Received support from the University of New Mexico Cancer Research and Treatment Center and is a recipient of National Institutes of Health Postdoctoral Training Fellowship T32 AI007538.

^¶ To whom correspondence should be addressed: Dept. of Cell Biology and Physiology, University of New Mexico, Albuquerque, NM 87131. Tel.: 505-272-5647; Fax: 505-272-1421; E-mail: eprossnitz{at}salud.unm.edu.

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