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

Cattaruzza, F., Cottrell, G.S. ORCID: https://orcid.org/0000-0001-9098-7627, 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 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.

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.
Item Type	Article
URI	https://reading-clone.eprints-hosting.org/id/eprint/30259
Item Type	Article
Refereed	Yes
Divisions	No Reading authors. Back catalogue items
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
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