Human mast cell proteases hydrolyze neurotensin, kinetensin and Leu5-enkephalin

Goldstein, Sanford M.; Leong, Jane; Bunnett, Nigel W.

doi:10.1016/0196-9781(91)90049-u

Cited by 33 publications

(16 citation statements)

References 29 publications

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“…However, it is in many cases uncertain whether these are true in vivo substrates for MC-CPA. For example, despite neurotensin being cleaved by MC-CPA in vitro [53,[60][61][62], MC-CPA did not seem to have any role in its degradation in vivo [53].…”

Section: Biological Substratesmentioning

confidence: 60%

“…Clearly, we anticipate that the next decade will unravel a more detailed picture concerning the biological role of MC-CPA, both in health and in disease. Modulation of dopamine signaling [53,[60][61][62] Endothelin-1 Vasoconstriction [6,67] Apolipoprotein B Cholesterol transport [68] Sarafotoxin 6b Venom (Asp) [6,56] Angiotensin I Vasoconstriction [60] Kinetensin Inflammatory mediator [60] Leu 5 -enkephalin Opioid receptor signaling [60] Neuromedin N Peptide derived from neurotensin [62] Xenopsin Hormonal and anti-microbial function [62] Note, although cleavage of these substrates have been demonstrated in vitro the functional significance of this has not been confirmed in vivo.…”

Section: Future Perspectivesmentioning

confidence: 97%

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Novel insights into the biological function of mast cell carboxypeptidase A

Pejler

Knight

Henningsson

et al. 2009

Trends in Immunology

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Section: Biological Substratesmentioning

confidence: 60%

Section: Future Perspectivesmentioning

confidence: 97%

Novel insights into the biological function of mast cell carboxypeptidase A

Pejler

Knight

Henningsson

et al. 2009

Trends in Immunology

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“…We provide pharmacological and genetic evidence that NT can contribute to mortality in mice subjected to severe caecal ligation and puncture (CLP), a model of acute septic peritonitis. 14 Mast cells (MCs) can be activated by several mechanisms in CLP and can promote survival in this setting, 15 ,16 ,17 and both TNF,18 ,19 ,20 and mouse MC protease-6 (mMCP-6) 21 have been reported to reduce mortality in CLP19 , 20 and/or other models of infection.18 ,21 Because certain MC-derived proteases can degrade NT, 22,23 we hypothesized that an additional mechanism by which MCs can promote survival in CLP is by reducing levels of NT. We now report evidence that strongly supports that hypothesis.…”

Section: Introductionmentioning

confidence: 99%

Neurotensin increases mortality and mast cells reduce neurotensin levels in a mouse model of sepsis

Piliponsky

Chen

Nishimura

et al. 2008

Nat Med

120

100

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Sepsis is a complex, incompletely understood and often fatal disorder, typically accompanied by hypotension, that is considered to represent a dysregulated host response to infection. Neurotensin (NT) is a 13-amino-acid peptide that, among its multiple effects, induces hypotension. We find that intraperitoneal and plasma concentrations of NT are increased in mice after severe cecal ligation and puncture (CLP), a model of sepsis, and that mice treated with a pharmacological antagonist of NT, or NT-deficient mice, show reduced mortality during severe CLP. In mice, mast cells can degrade NT and reduce NT-induced hypotension and CLP-associated mortality, and optimal expression of these effects requires mast cell expression of neurotensin receptor 1 and neurolysin. These findings show that NT contributes to sepsis-related mortality in mice during severe CLP and that mast cells can lower NT concentrations, and suggest that mast cell-dependent reduction in NT levels contributes to the ability of mast cells to enhance survival after CLP.

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“…Mast cell carboxypeptidase A (CPA) was shown to be the enzyme responsible for this rapid degradation [9]. It is also responsible for the degradation of other peptides [10]. …”

Section: Introductionmentioning

confidence: 99%

Inhibition of Neurotensin-Stimulated Mast Cell Secretion and Carboxypeptidase A Activity by the Peptide Inhibitor of Carboxypeptidase A and Neurotensin-Receptor Antagonist SR 48692

Miller

Cochrane

Feldberg

et al. 1998

Int Arch Allergy Immunol

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Background: Neurotensin (NT), a peptide found in brain and several peripheral tissues, is a potent stimulus for mast cell secretion and its actions are blocked by the specific NT receptor antagonist, SR 48692. Subsequent to stimulation, NT is rapidly degraded by mast cell carboxypeptidase A (CPA). In the experiments described here, we tested for the involvement of CPA activity in the activation of mast cell secretion by the peptide, NT. Methods: Mast cells were isolated from the peritoneal and pleural cavities of rats, purified over metrizamide gradients and incubated at 37 °C in Locke solution or Locke containing the appropriate inhibitors. For some experiments, media derived from mast cells stimulated by compound 48/80 were used as a source of mast cell CPA activity. Results: Treatment of mast cells with the highly specific peptide inhibitor of CPA derived from potato (PCI) inhibited histamine release in response to NT and NT^8–13 (the biologically active region of NT). This inhibition required some 20 min to develop and was only partially reversed by a 20-min wash period. PCI (10 μM) did not inhibit histamine release in response to NT^1–12, bardykinin, compound 48/80, the calcium ionophore, A23187, or anti-IgE serum. PCI also inhibited mast cell CPA activity. SR 48692, a highly selective antagonist of the brain NT receptor and of NT-stimulated mast cell secretion, also inhibited mast cell CPA activity as well as bovine pancreatic CPA activity in a concentration-dependent manner. Discussion: It is suggested that the mast cell binding site for NT and the active site for CPA may share similar characteristics. The results are discussed in terms of NT mechanism of action on the mast cell.

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Human mast cell proteases hydrolyze neurotensin, kinetensin and Leu5-enkephalin

Cited by 33 publications

References 29 publications

Novel insights into the biological function of mast cell carboxypeptidase A

Novel insights into the biological function of mast cell carboxypeptidase A

Neurotensin increases mortality and mast cells reduce neurotensin levels in a mouse model of sepsis

Inhibition of Neurotensin-Stimulated Mast Cell Secretion and Carboxypeptidase A Activity by the Peptide Inhibitor of Carboxypeptidase A and Neurotensin-Receptor Antagonist SR 48692

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