Accessibility navigation


Endothelin-converting enzyme 1 promotes re-sensitization of neurokinin 1 receptor-dependent neurogenic inflammation

Cattaruzza, F., Cottrell, G.S., Vaksman, N. and Bunnett, N.W. (2009) Endothelin-converting enzyme 1 promotes re-sensitization of neurokinin 1 receptor-dependent neurogenic inflammation. British Journal of Pharmacology, 156 (5). pp. 730-739. ISSN 1476-5381

Full text not archived in this repository.

It is advisable to refer to the publisher's version if you intend to cite from this work. See Guidance on citing.

To link to this item DOI: 10.1111/j.1476-5381.2008.00039.x

Abstract/Summary

BACKGROUND AND PURPOSE: The metalloendopeptidase endothelin-converting enzyme 1 (ECE-1) is prominently expressed in the endothelium where it converts big endothelin to endothelin-1, a vasoconstrictor peptide. Although ECE-1 is found in endosomes in endothelial cells, the role of endosomal ECE-1 is unclear. ECE-1 degrades the pro-inflammatory neuropeptide substance P (SP) in endosomes to promote recycling and re-sensitization of its neurokinin 1 (NK(1)) receptor. We investigated whether ECE-1 regulates NK(1) receptor re-sensitization and the pro-inflammatory effects of SP in the endothelium. EXPERIMENTAL APPROACH: We examined ECE-1 expression, SP trafficking and NK(1) receptor re-sensitization in human microvascular endothelial cells (HMEC-1), and investigated re-sensitization of SP-induced plasma extravasation in rats. KEY RESULTS: HMEC-1 expressed all four ECE-1 isoforms (a-d), and fluorescent SP trafficked to early endosomes containing ECE-1b/d. The ECE-1 inhibitor SM-19712 prevented re-sensitization of SP-induced Ca2+ signals in HMEC-1 cells. Immunoreactive ECE-1 and NK(1) receptors co-localized in microvascular endothelial cells in the rat. SP-induced extravasation of Evans blue in the urinary bladder, skin and ears of the rat desensitized when the interval between two SP injections was 10 min, and re-sensitized after 480 min. SM-19712 inhibited this re-sensitization. CONCLUSIONS AND IMPLICATIONS: By degrading endocytosed SP, ECE-1 promotes the recycling and re-sensitization of NK(1) receptors in endothelial cells, and thereby induces re-sensitization of the pro-inflammatory effects of SP. Thus, ECE-1 inhibitors may ameliorate the pro-inflammatory actions of SP.

Item Type:Article
Refereed:Yes
Divisions:No Reading authors. Back catalogue items
ID Code:30259
Uncontrolled Keywords:Animals Aspartic Acid Endopeptidases/biosynthesis/*physiology Calcium/metabolism Calcium Signaling Capillary Permeability Cell Line Ear/blood supply Endocytosis Endosomes/metabolism Endothelial Cells/metabolism Endothelium, Vascular/cytology Humans Male Metalloendopeptidases/biosynthesis/*physiology Microvessels/cytology Neurogenic Inflammation/*metabolism Rats Rats, Sprague-Dawley Receptors, Neurokinin-1/biosynthesis/*physiology Skin/blood supply Substance P/metabolism Urinary Bladder/blood supply
Additional Information:Cattaruzza, F Cottrell, G S Vaksman, N Bunnett, N W DK39957/DK/NIDDK NIH HHS/ DK43207/DK/NIDDK NIH HHS/ England Br J Pharmacol. 2009 Mar;156(5):730-9. Epub 2009 Feb 6.
Publisher:Wiley for the British Pharmacological Society

University Staff: Request a correction | Centaur Editors: Update this record

Page navigation