Endothelin-converting enzyme 1 and beta-arrestins exert spatiotemporal control of substance P-induced inflammatory signals

Dane D Jensen, Michelle Louise Halls, Jane E Murphy, Meritxell Canals, Fiore Cattaruzza, Daniel Philip Poole, Tina Marie Lieu, Hon-Wai Koon, Charalabos Pothoulakis, Nigel William Bunnett

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Although the intracellular trafficking of G protein-coupled receptors controls specific signaling events, it is unclear how the spatiotemporal control of signaling contributes to complex pathophysiological processes such as inflammation. By using bioluminescence resonance energy transfer and superresolution microscopy, we found that substance P (SP) induces the association of the neurokinin 1 receptor(NK1R) with two classes of proteins that regulate SP signaling from plasma and endosomal membranes: the scaffolding proteins ?-arrestin (?ARRs) 1 and 2 and thetransmembrane metallopeptidases ECE-1c and ECE-1d. In HEK293 cells and non-transformed human colonocytes, we observed that G protein-coupled receptor kinase 2 and ?ARR1/2 terminate plasma membrane Ca2+ signaling and initiate receptor trafficking to endosomes that is necessary for sustained activation of ERKs in the nucleus. ?ARRs deliver the SP-NK1R endosomes, where ECE-1 associates with the complex, degrades SP, and allows the NK1R, freed from ?ARRs, to recycle. Thus, both ECE-1 and ?ARRs mediate the resensitization of NK1R Ca2+ signaling at the plasma membrane. Sustained exposure of colonocytes to SP activates NF-?B and stimulates IL-8 secretion. This proinflammatory signaling is unaffected by inhibition of the endosomal ERK pathway but is suppressed by ECE-1 inhibition or ?ARR2 knockdown. Inhibition of protein phosphatase 2A, which also contributes to sustained NK1R signaling at the plasma membrane, similarly attenuates IL-8 secretion. Thus, the primary function of ?ARRs and ECE-1in SP-dependent inflammatory signaling is to promote resensitization, which allows the sustained NK1R signaling from the plasma membrane that drives inflammation.
Original languageEnglish
Pages (from-to)20283 - 20294
Number of pages12
JournalJournal of Biological Chemistry
Volume289
Issue number29
DOIs
Publication statusPublished - 2014

Cite this

Jensen, Dane D ; Halls, Michelle Louise ; Murphy, Jane E ; Canals, Meritxell ; Cattaruzza, Fiore ; Poole, Daniel Philip ; Lieu, Tina Marie ; Koon, Hon-Wai ; Pothoulakis, Charalabos ; Bunnett, Nigel William. / Endothelin-converting enzyme 1 and beta-arrestins exert spatiotemporal control of substance P-induced inflammatory signals. In: Journal of Biological Chemistry. 2014 ; Vol. 289, No. 29. pp. 20283 - 20294.
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title = "Endothelin-converting enzyme 1 and beta-arrestins exert spatiotemporal control of substance P-induced inflammatory signals",
abstract = "Although the intracellular trafficking of G protein-coupled receptors controls specific signaling events, it is unclear how the spatiotemporal control of signaling contributes to complex pathophysiological processes such as inflammation. By using bioluminescence resonance energy transfer and superresolution microscopy, we found that substance P (SP) induces the association of the neurokinin 1 receptor(NK1R) with two classes of proteins that regulate SP signaling from plasma and endosomal membranes: the scaffolding proteins ?-arrestin (?ARRs) 1 and 2 and thetransmembrane metallopeptidases ECE-1c and ECE-1d. In HEK293 cells and non-transformed human colonocytes, we observed that G protein-coupled receptor kinase 2 and ?ARR1/2 terminate plasma membrane Ca2+ signaling and initiate receptor trafficking to endosomes that is necessary for sustained activation of ERKs in the nucleus. ?ARRs deliver the SP-NK1R endosomes, where ECE-1 associates with the complex, degrades SP, and allows the NK1R, freed from ?ARRs, to recycle. Thus, both ECE-1 and ?ARRs mediate the resensitization of NK1R Ca2+ signaling at the plasma membrane. Sustained exposure of colonocytes to SP activates NF-?B and stimulates IL-8 secretion. This proinflammatory signaling is unaffected by inhibition of the endosomal ERK pathway but is suppressed by ECE-1 inhibition or ?ARR2 knockdown. Inhibition of protein phosphatase 2A, which also contributes to sustained NK1R signaling at the plasma membrane, similarly attenuates IL-8 secretion. Thus, the primary function of ?ARRs and ECE-1in SP-dependent inflammatory signaling is to promote resensitization, which allows the sustained NK1R signaling from the plasma membrane that drives inflammation.",
author = "Jensen, {Dane D} and Halls, {Michelle Louise} and Murphy, {Jane E} and Meritxell Canals and Fiore Cattaruzza and Poole, {Daniel Philip} and Lieu, {Tina Marie} and Hon-Wai Koon and Charalabos Pothoulakis and Bunnett, {Nigel William}",
year = "2014",
doi = "10.1074/jbc.M114.578179",
language = "English",
volume = "289",
pages = "20283 -- 20294",
journal = "Journal of Biological Chemistry",
issn = "1083-351X",
publisher = "American Society for Biochemistry and Molecular Biology",
number = "29",

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Jensen, DD, Halls, ML, Murphy, JE, Canals, M, Cattaruzza, F, Poole, DP, Lieu, TM, Koon, H-W, Pothoulakis, C & Bunnett, NW 2014, 'Endothelin-converting enzyme 1 and beta-arrestins exert spatiotemporal control of substance P-induced inflammatory signals' Journal of Biological Chemistry, vol. 289, no. 29, pp. 20283 - 20294. https://doi.org/10.1074/jbc.M114.578179

Endothelin-converting enzyme 1 and beta-arrestins exert spatiotemporal control of substance P-induced inflammatory signals. / Jensen, Dane D; Halls, Michelle Louise; Murphy, Jane E; Canals, Meritxell; Cattaruzza, Fiore; Poole, Daniel Philip; Lieu, Tina Marie; Koon, Hon-Wai; Pothoulakis, Charalabos; Bunnett, Nigel William.

In: Journal of Biological Chemistry, Vol. 289, No. 29, 2014, p. 20283 - 20294.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Endothelin-converting enzyme 1 and beta-arrestins exert spatiotemporal control of substance P-induced inflammatory signals

AU - Jensen, Dane D

AU - Halls, Michelle Louise

AU - Murphy, Jane E

AU - Canals, Meritxell

AU - Cattaruzza, Fiore

AU - Poole, Daniel Philip

AU - Lieu, Tina Marie

AU - Koon, Hon-Wai

AU - Pothoulakis, Charalabos

AU - Bunnett, Nigel William

PY - 2014

Y1 - 2014

N2 - Although the intracellular trafficking of G protein-coupled receptors controls specific signaling events, it is unclear how the spatiotemporal control of signaling contributes to complex pathophysiological processes such as inflammation. By using bioluminescence resonance energy transfer and superresolution microscopy, we found that substance P (SP) induces the association of the neurokinin 1 receptor(NK1R) with two classes of proteins that regulate SP signaling from plasma and endosomal membranes: the scaffolding proteins ?-arrestin (?ARRs) 1 and 2 and thetransmembrane metallopeptidases ECE-1c and ECE-1d. In HEK293 cells and non-transformed human colonocytes, we observed that G protein-coupled receptor kinase 2 and ?ARR1/2 terminate plasma membrane Ca2+ signaling and initiate receptor trafficking to endosomes that is necessary for sustained activation of ERKs in the nucleus. ?ARRs deliver the SP-NK1R endosomes, where ECE-1 associates with the complex, degrades SP, and allows the NK1R, freed from ?ARRs, to recycle. Thus, both ECE-1 and ?ARRs mediate the resensitization of NK1R Ca2+ signaling at the plasma membrane. Sustained exposure of colonocytes to SP activates NF-?B and stimulates IL-8 secretion. This proinflammatory signaling is unaffected by inhibition of the endosomal ERK pathway but is suppressed by ECE-1 inhibition or ?ARR2 knockdown. Inhibition of protein phosphatase 2A, which also contributes to sustained NK1R signaling at the plasma membrane, similarly attenuates IL-8 secretion. Thus, the primary function of ?ARRs and ECE-1in SP-dependent inflammatory signaling is to promote resensitization, which allows the sustained NK1R signaling from the plasma membrane that drives inflammation.

AB - Although the intracellular trafficking of G protein-coupled receptors controls specific signaling events, it is unclear how the spatiotemporal control of signaling contributes to complex pathophysiological processes such as inflammation. By using bioluminescence resonance energy transfer and superresolution microscopy, we found that substance P (SP) induces the association of the neurokinin 1 receptor(NK1R) with two classes of proteins that regulate SP signaling from plasma and endosomal membranes: the scaffolding proteins ?-arrestin (?ARRs) 1 and 2 and thetransmembrane metallopeptidases ECE-1c and ECE-1d. In HEK293 cells and non-transformed human colonocytes, we observed that G protein-coupled receptor kinase 2 and ?ARR1/2 terminate plasma membrane Ca2+ signaling and initiate receptor trafficking to endosomes that is necessary for sustained activation of ERKs in the nucleus. ?ARRs deliver the SP-NK1R endosomes, where ECE-1 associates with the complex, degrades SP, and allows the NK1R, freed from ?ARRs, to recycle. Thus, both ECE-1 and ?ARRs mediate the resensitization of NK1R Ca2+ signaling at the plasma membrane. Sustained exposure of colonocytes to SP activates NF-?B and stimulates IL-8 secretion. This proinflammatory signaling is unaffected by inhibition of the endosomal ERK pathway but is suppressed by ECE-1 inhibition or ?ARR2 knockdown. Inhibition of protein phosphatase 2A, which also contributes to sustained NK1R signaling at the plasma membrane, similarly attenuates IL-8 secretion. Thus, the primary function of ?ARRs and ECE-1in SP-dependent inflammatory signaling is to promote resensitization, which allows the sustained NK1R signaling from the plasma membrane that drives inflammation.

UR - http://www.jbc.org/content/289/29/20283.full.pdf+html

U2 - 10.1074/jbc.M114.578179

DO - 10.1074/jbc.M114.578179

M3 - Article

VL - 289

SP - 20283

EP - 20294

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 1083-351X

IS - 29

ER -