Identification of the C3a Receptor (C3AR1) as the Target of the VGF-derived Peptide TLQP-21 in Rodent Cells

Hannedouche, Sébastien; Beck, Valerie; Leighton-Davies, Juliet; Beibel, Martin; Roma, Guglielmo; Oakeley, Edward J.; Lannoy, Vincent; Bernard, Jérôme; Hamon, Jacques; Barbieri, Samuel; Preuß, Inga; Lasbennes, Marie-Christine; Sailer, Andreas W.; Suply, Thomas; Seuwen, Klaus; Parker, Christian N.; Bassilana, Frédéric

doi:10.1074/jbc.m113.497214

Cited by 87 publications

(125 citation statements)

References 42 publications

(48 reference statements)

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“…Studies in this area were perhaps the first reports of functional antagonism between C3a and C5a at the molecular level. Until recently, C3a was thought to be the only ligand for C3aR; however, the neuropeptide TLQP-21, a cleavage fragment of the VGL propeptide, was shown to bind and activate murine C3aR through conformational change of the ligand upon receptor binding (25,26).…”

mentioning

confidence: 99%

Is the Complement Activation Product C3a a Proinflammatory Molecule? Re-evaluating the Evidence and the Myth

Coulthard

Woodruff

2015

The Journal of Immunology

234

200

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The complement activation product C3a is often described as a proinflammatory mediator, alongside its downstream cousin, C5a. However, emerging studies show that C3a has several anti-inflammatory facets in vivo. For example, in the acute inflammatory response, C3a acts in direct opposition to C5a, through preventing the accumulation of neutrophils in inflamed tissues by independently regulating their mobilization. This acute, protective, and opposing activity of C3a to C5a is also illustrated in models of septicemia. In this article, we reinvestigate the discovery and original classification of C3a as a proinflammatory mediator and highlight the emerging studies demonstrating anti-inflammatory effects for C3a in the immune response. It is our hope that this review illuminates these apparently contradictory roles for C3a and challenges the general dogma surrounding C3a, which, historically, has ubiquitously been described as a proinflammatory mediator. In light of this, we urge investigators to use “inflammatory modulator” as the descriptor for C3a.

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mentioning

confidence: 99%

Is the Complement Activation Product C3a a Proinflammatory Molecule? Re-evaluating the Evidence and the Myth

Coulthard

Woodruff

2015

The Journal of Immunology

234

200

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“…Another future problem for the translational stroke research is to identify the receptor and the downstream signaling pathways of VGF-derived bioactive peptides for the functions of neuroprotection and neural plasticity. Recently, possible candidates for receptors of VGFderived bioactive peptides were reported [32,33]. Taken together, we here propose the application of VGF could be one of the promising therapeutic targets for stroke therapy to promote recovery when those problems are solved in the future.…”

Section: Discussionmentioning

confidence: 67%

VGF, Which Is Induced Transcriptionally in Stroke Brain, Enhances Neurite Extension and Confers Protection Against Ischemia In Vitro

Sakamoto

Miyazaki

Kitajo

et al. 2015

Transl. Stroke Res.

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Ischemic stroke is a devastating neural event as currently no therapies other than physical rehabilitation are available to enhance recovery after stroke. To identify endogenous mediators to repair stroke brain, we performed the expression profiling analysis of transcripts in the mouse photothrombotic stroke brain. Based on real-time PCR analysis, we found VGF, identified as a nerve growth factor (NGF)-regulated transcript, was induced transcriptionally in stroke brain at 1-7 days after insult. The immunoreactivites of VGF were observed in the neurons around the ischemic core of stroke brain. Experiments with various inhibitors and plasmid transfections indicated that cAMP response element binding protein-mediated complex signaling pathways are possibly implicated in the NGF-mediated VGF expressions in vitro. Furthermore, the over-expression of VGF promoted neurite extensions and conferred protections from ischemic stress in vitro. These findings raise the possibility the application of VGF could be one of the promising therapeutic strategies to enhance recovery after stroke.

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“…Recently, more interest has been paid to classify the so far unknown receptor for TLQP-21. This has led to the identification of complement system receptors as candidate receptors for TLQP-21 in rodents, and in this context supporting that TLQP-21 plays a role in hypersensitivity and inflammation [21,22]. Expression of the complement receptors have been demonstrated in several immune cells [23,24], but not in pancreatic islets of Langerhans to our knowledge.…”

Section: Endocrine Researchmentioning

confidence: 74%

The VGF-Derived Neuropeptide TLQP-21 Shows No Impact on Hormone Secretion in the Isolated Perfused Rat Pancreas

Svendsen

Holst

2015

Horm Metab Res

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TLQP-21 is a VGF-derived neuropeptide proposed to be involved in regulation of metabolism. More specifically it has been suggested that TLQP-21 has the ability to enhance glucose stimulated insulin secretion, making it a candidate for treatment of patients with type 2 diabetes.In this study, we investigated the impact of TLQP-21 on insulin, glucagon, and somatostatin secretion in the perfused rat pancreas. We found that administration of 5 and 50 nM TLQP-21 had no impact on pancreatic hormone secretion at 3.5 or 8 mM glucose levels. Increasing TLQP-21 (200 nM) and glucose concentration (3.5 and 16 mM) led to a nonsignificant decrease in glucagon secretion, though insulin and somatostatin secretory patterns remained unaffected. In a final set of experiments, perfusions were performed with infusion of 50 and 1 000 nM TLQP-21 to ensure sufficient stimulation. However, administration of TLQP-21 under this setup showed no impact on the pancreatic hormone secretion either. In conclusion, the outcome of this study does not concur with previous findings, suggesting that the effect of TLQP-21 does not directly involve silent hormone secretion.

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Identification of the C3a Receptor (C3AR1) as the Target of the VGF-derived Peptide TLQP-21 in Rodent Cells

Cited by 87 publications

References 42 publications

Is the Complement Activation Product C3a a Proinflammatory Molecule? Re-evaluating the Evidence and the Myth

Is the Complement Activation Product C3a a Proinflammatory Molecule? Re-evaluating the Evidence and the Myth

VGF, Which Is Induced Transcriptionally in Stroke Brain, Enhances Neurite Extension and Confers Protection Against Ischemia In Vitro

The VGF-Derived Neuropeptide TLQP-21 Shows No Impact on Hormone Secretion in the Isolated Perfused Rat Pancreas

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