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

Abstract

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 (NK1) receptor. We investigated whether ECE-1 regulates NK1 receptor re-sensitization and the pro-inflammatory effects of SP in the endothelium. Experimental approach: We examined ECE-1 expression, SP trafficking and NK1 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 NK1 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 NK1 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.

Endothelin-converting Enzymes Degrade Intracellular β-Amyloid Produced within the Endosomal/Lysosomal Pathway and Autophagosomes*

“…In addition to its strong expression in endothelial cells, ECE-1 is expressed in neurons in different areas of the CNS, including areas relevant to AD, and contributes to the metabolism of different neuropeptides as well as receptor resensitization within the endosomal system (45,46). The intracellular ECE-1d and ECE-1b isoforms are localized in recycling endosomes with ECE-1b present also in late endosomes.…”

Neural peptidase endothelin-converting enzyme 1 regulates endothelin 1–induced pruritus

“…Thus, like SP, CGRP, or somatostatin, ECE-1 internalized with the ET-1/ETAR complex into early endosomes, cleaved ET-1, and may thereby regulate the function of ET-1 in murine DRG neurons during an itch response (27,33). Recently, it has been shown that ECE-1 participates in the modulation of neurogenic inflammation in mice in vivo (66). However, we believe that the results of the current study demonstrate for the first time that ECE-1 is also directly involved in ET-1-mediated pruritus and neuronal cell signaling in vivo.…”

Endosomes: A legitimate platform for the signaling train

“…By degrading SP and CGRP in acidified endosomes, ECE-1 promotes recycling and resensitization of receptors that mediate neurogenic inflammation and pain (52,53). An ECE-1 inhibitor prevents resensitization of SP-induced plasma extravasation, providing evidence for an antiinflammatory effect of ECE-1 inhibitors (53,97). Thus, in the case of ␤arrs and ECE-1, therapies that specifically target GPCR signaling in endosomes without affecting signaling at the plasma membrane are a viable and novel pharmacological strategy.…”

“…This strategy may offer improved selectivity with fewer side effects than targeting more proximal steps of receptor signaling. Indeed, drugs that either target endosomal signaling events (53,(95)(96)(97) or that are specifically delivered to endosomes (98) have powerful effects. The challenge will be to design drugs that target endosomal signaling relevant to disease.…”