Arrestins block G protein-coupled receptor-mediated apoptosis
Arrestins block G protein-coupled receptor-mediated apoptosis
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DOI：
10.1074/jbc.m402121200
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发表时间：
2004-06-04
影响因子：
4.8
通讯作者：
Prossnitz, ER
中科院分区：
文献类型：
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作者：
Revankar, CM;Vines, CM;Prossnitz, ER
G蛋白（异源三聚体鸟嘌呤核苷酸结合蛋白）偶联受体（GPCR）通过G蛋白、GPCR激酶和抑制蛋白的联合作用激活许多细胞信号。虽然抑制蛋白传统上被认为是介导GPCR脱敏，但现在已显示它们在许多GPCR的内化、运输和信号传导中发挥重要作用。我们证明，在缺乏抑制蛋白的细胞中，包括N-甲酰肽受体（FPR）在内的众多GPCR的刺激启动了快速的细胞变圆，膜联蛋白V阳性和caspase激活，随后细胞死亡。细胞凋亡反应由G蛋白信号传导启动，涉及磷酸肌醇3-激酶、促分裂原活化蛋白激酶和c-Src的活化，导致细胞色素c从线粒体释放，并最终激活半胱天冬酶9和半胱天冬酶3。用arrestin-2或arrestin-3重建完全足以防止FPR介导的细胞凋亡。令人惊讶的是，FPR的非脱敏和非内化突变体不能启动细胞凋亡，表明受体磷酸化和内化，而不仅仅是由于缺乏脱敏的慢性激活，是FPR诱导细胞凋亡的关键决定因素。我们进一步证明，这种反应不是FPR所独有的，还有许多其他GPCR，包括V2加压素、血管紧张素II（1A型）和CXCR 2受体，能够在刺激后启动凋亡，而GPCR如β（2）-肾上腺素能受体和CXCR 4不能启动凋亡信号。这些数据首次表明，抑制蛋白在抑制GPCR介导的细胞凋亡中发挥关键和完全出乎意料的作用，我们表明这是在缺乏抑制蛋白的情况下GPCR介导的细胞活化的常见结果。
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 beta(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.