N-Formyl Peptide Receptors Internalize but Do Not Recycle in the Absence of Arrestins

Vines, Charlotte M.; Revankar, Chetana M.; Maestas, Diane C.; LaRusch, Leah L.; Cimino, Daniel F.; Kohout, Trudy A.; Lefkowitz, Robert J.; Prossnitz, Eric R.

doi:10.1074/jbc.c300291200

Cited by 99 publications

(135 citation statements)

References 33 publications

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“…Our results demonstrated that FPR internalization was unaffected by the absence of arrestins, indicating that the FPR despite binding arrestin in arrestin-replete cells does not require arrestin to internalize (9). However, further studies revealed that FPR recycling required arrestin, the first demonstration that arrestin is required for the proper trafficking of a GPCR back to the cell surface following internalization.…”

mentioning

confidence: 70%

“…Mouse embryonic fibroblasts with and without ␤-arrestins were established as described previously (7) and generously provided by Dr. Robert Lefkowitz. Stable clones expressing the FPR were generated and cultured as described previously (9).…”

Section: Methodsmentioning

confidence: 99%

“…Although many GPCRs, exemplified by the ␤ 2 -adrenergic receptor, internalize in an arrestin-dependent manner (7), a growing number of GPCRs (e.g. protease-activated receptor 1 (8) and the N-formyl peptide receptor (FPR) (9)) are capable of undergoing internalization in an arrestin-independent manner. In the case of the FPR, a chemoattractant leukocyte GPCR (10,11), numerous lines of evidence including the use of dominant negative arrestin constructs (arrestin-2-(319 -418)) (12) and partially phosphorylated receptor mutants (13), which internalize in the absence of demonstrable arrestin binding, had suggested that receptor internalization does not require arrestin binding despite the observation that the FPR directly binds arrestins and colocalizes with them during receptor internalization (14 -18).…”

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confidence: 99%

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Arrestins Block G Protein-coupled Receptor-mediated Apoptosis

Revankar¹,

Vines²,

Cimino

et al. 2004

Journal of Biological Chemistry

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119

107

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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.

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confidence: 70%

Section: Methodsmentioning

confidence: 99%

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Arrestins Block G Protein-coupled Receptor-mediated Apoptosis

Revankar¹,

Vines²,

Cimino

et al. 2004

Journal of Biological Chemistry

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119

107

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“…This is important because various examples demonstrate that β-arrestin2 recruitment and receptor internalization can be independent processes, as it is the case e.g. with the PAR1 thrombin receptor (Paing et al, 2002), the CXCR2 chemokine receptor (Fan et al, 2001;Zhao et al, 2004), the N-formyl peptide receptor (FPR) (Vines et al, 2003), or at high agonist concentration the AT 1 angiotensin receptor (Gaborik et al, 2001;Hunyady and Catt, 2006;Zhang et al, 1996). Therefore, it is important to study directly the β-arrestin dependence of CB 1 R internalization.…”

Section: Discussionmentioning

confidence: 99%

Differential β-arrestin2 requirements for constitutive and agonist-induced internalization of the CB1 cannabinoid receptor

Gyombolai

Boros

Hunyady

et al. 2013

Molecular and Cellular Endocrinology

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CB 1 cannabinoid receptor (CB 1 R) undergoes both constitutive and agonist-induced internalization, but the underlying mechanisms of these processes and the role of β-arrestins in the regulation of CB 1 R function are not completely understood. In this study, we followed CB 1 R internalization using confocal microscopy and bioluminescence resonance energy transfer measurements in HeLa and Neuro-2a cells. We found that upon activation CB 1 R binds β-arrestin2 (β-arr2), but not β-arrestin1. Furthermore, both the expression of dominant-negative β-arr2 (β-arr2-V54D) and siRNA-mediated knock-down of β-arr2 impaired the agonist-induced internalization of CB 1 R. In contrast, neither β-arr2-V54D nor β-arr2-specific siRNA had a significant effect on the constitutive internalization of CB 1 R. However, both constitutive and agonist-induced internalization of CB 1 R were impaired by siRNA-mediated depletion of clathrin heavy chain. We conclude that although clathrin is required for both constitutive and agonist-stimulated internalization of CB 1 R, β-arr2 binding is only required for agonist-induced internalization of the receptor suggesting that the molecular mechanisms underlying constitutive and agonist-induced internalization of CB 1 R are different.

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“…However, there are many exceptions to this central paradigm because several GPCRs do not require arrestins to get internalized. Many examples have been described such as the serotonin receptor 5-HT 2A (Gray et al, 2001), protease-activated receptor PAR1 (Paing et al, 2002), prostacyclin receptor IP (Smyth et al, 2000), leukotriene B4 receptor BLT1 , formyl-peptide receptor FPR (Vines et al, 2003) or muscarinic receptor M2 (Vogler et al, 1999). SUCNR1 was originally described as being coupled to both G i and G q proteins in human embryonic kidney (HEK293) cells (He et al, 2004).…”

Section: Succinate Receptor 1 Signaling Pathwaysmentioning

confidence: 99%

Insight into SUCNR1 (GPR91) structure and function

Gilissen

Jouret

Pirotte

et al. 2016

Pharmacology & Therapeutics

111

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SUCNR1 (or GPR91) belongs to the family of G protein-coupled receptors (GPCR), which represents the largest group of membrane proteins in human genome. The majority of marketed drugs targets GPCRs, directly or indirectly. SUCNR1 has been classified as an orphan receptor until a landmark study paired it with succinate, a citric acid cycle intermediate.According to the current paradigm, succinate triggers SUCNR1 signaling pathways to indicate local stress that may affect cellular metabolism. SUCNR1 implication has been well documented in renin-induced hypertension, ischemia/reperfusion injury, inflammation and immune response, platelet aggregation and retinal angiogenesis. In addition, the SUCNR1-induced increase of blood pressure may contribute to diabetic nephropathy or cardiac hypertrophy.The understanding of SUCNR1 activation, signaling pathways and functions remains largely elusive, which calls for deeper investigations. SUCNR1 shows a high potential as an innovative drug target and is probably an important regulator of basic physiology. In order to achieve the full characterization of this receptor, more specific pharmacological tools such as small-molecules modulators will represent an important asset. In this review, we describe the structural features of SUCNR1, its current ligands and putative binding pocket. We give an exhaustive overview of the known and hypothetical signaling partners of the receptor in different in vitro and in vivo systems. The link between SUCNR1 intracellular pathways and its pathophysiological roles are also extensively discussed.

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N-Formyl Peptide Receptors Internalize but Do Not Recycle in the Absence of Arrestins

Cited by 99 publications

References 33 publications

Arrestins Block G Protein-coupled Receptor-mediated Apoptosis

Arrestins Block G Protein-coupled Receptor-mediated Apoptosis

Differential β-arrestin2 requirements for constitutive and agonist-induced internalization of the CB1 cannabinoid receptor

Insight into SUCNR1 (GPR91) structure and function

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