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Papers In Press, published online ahead of print March 29, 2004
Cell Biology and Physiology, University of New Mexico, Albuquerque, NM 87131
Corresponding Author: eprossnitz{at}Salud.unm.edu
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, 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 -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, being capable of initiating apoptosis upon stimulation, whereas GPCRs such as the ß2 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.
J. Biol. Chem, 10.1074/jbc.M402121200
Submitted on February 26, 2004
Revised on March 29, 2004
Accepted on March 29, 2004
Arrestins block G protein-coupled receptor-mediated apoptosis
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