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Neural peptidase endothelin-converting enzyme 1 regulates endothelin 1–induced pruritus
Makiko Kido-Nakahara, … , Masutaka Furue, Martin Steinhoff
Makiko Kido-Nakahara, … , Masutaka Furue, Martin Steinhoff
Published May 8, 2014
Citation Information: J Clin Invest. 2014;124(6):2683-2695. https://doi.org/10.1172/JCI67323.
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Research Article Neuroscience Article has an altmetric score of 16

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

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Abstract

In humans, pruritus (itch) is a common but poorly understood symptom in numerous skin and systemic diseases. Endothelin 1 (ET-1) evokes histamine-independent pruritus in mammals through activation of its cognate G protein–coupled receptor endothelin A receptor (ETAR). Here, we have identified neural endothelin–converting enzyme 1 (ECE-1) as a key regulator of ET-1–induced pruritus and neural signaling of itch. We show here that ETAR, ET-1, and ECE-1 are expressed and colocalize in murine dorsal root ganglia (DRG) neurons and human skin nerves. In murine DRG neurons, ET-1 induced internalization of ETAR within ECE-1–containing endosomes. ECE-1 inhibition slowed ETAR recycling yet prolonged ET-1–induced activation of ERK1/2, but not p38. In a murine itch model, ET-1–induced scratching behavior was substantially augmented by pharmacological ECE-1 inhibition and abrogated by treatment with an ERK1/2 inhibitor. Using iontophoresis, we demonstrated that ET-1 is a potent, partially histamine-independent pruritogen in humans. Immunohistochemical evaluation of skin from prurigo nodularis patients confirmed an upregulation of the ET-1/ETAR/ECE-1/ERK1/2 axis in patients with chronic itch. Together, our data identify the neural peptidase ECE-1 as a negative regulator of itch on sensory nerves by directly regulating ET-1–induced pruritus in humans and mice. Furthermore, these results implicate the ET-1/ECE-1/ERK1/2 pathway as a therapeutic target to treat pruritus in humans.

Authors

Makiko Kido-Nakahara, Jörg Buddenkotte, Cordula Kempkes, Akihiko Ikoma, Ferda Cevikbas, Tasuku Akiyama, Frank Nunes, Stephan Seeliger, Burcu Hasdemir, Christian Mess, Timo Buhl, Mathias Sulk, Frank-Ulrich Müller, Dieter Metze, Nigel W. Bunnett, Aditi Bhargava, Earl Carstens, Masutaka Furue, Martin Steinhoff

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Figure 3

ECE-1 is important for the recycling of ETAR in DRG neurons.

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ECE-1 is important for the recycling of ETAR in DRG neurons.
DRG neurons...
DRG neurons were cultured with ET-1 in the presence or absence of ECE-1 inhibitor. (A) Membrane-bound ETAR (arrows) internalized and colocalized with ECE-1 (arrowheads) in cytosolic vesicles of DRG neurons within 10 minutes after ET-1 stimulation. Recovery of the receptor on the plasma membrane was observed 60 minutes after ET-1 application (arrow). Scale bar: 30 μm. (B) ECE-1 inhibitor SM-19712 did not affect initial internalization of ETAR (arrows, arrowheads), but prevented recycling of ETAR to the plasma membrane. Scale bar: 30 μm. (C) Time dependence of ETAR translocation in DRG neurons in response to ET-1 (100 nM). In unstimulated cells, ETAR was mainly located at the plasma membrane. ET-1 stimulation for 10 minutes induced translocation of ETAR from the plasma membrane to the cytosol. Immunofluorescence for ETAR reappeared at the plasma membrane 60 minutes after stimulation (black bars). Costimulation with the ECE-1 inhibitor SM-19712 (10 μM) inhibited relocation of ETAR immunofluorescence to the plasma membrane (n = 10 cells/group, error bars indicate ± SEM, Student’s t test, **P < 0.01; ***P < 0.001). Subcellular distribution was analyzed from captured images using ImageJ software. (D) ECE-1 degraded ET-1 at endosomal pH 5.5, but not at pH 7.4. Degradation of ET-1 by rhECE-1 at pH 5.5 and pH 7.4 was assessed by HPLC. (E) ET-1 was hydrolyzed by ECE-1 at Asp18-Ile19.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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