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

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...

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Bibliographic Details
Published in:The Journal of clinical investigation 2014-06, Vol.124 (6), p.2683-2695
Main Authors: Kido-Nakahara, Makiko, Buddenkotte, Jörg, Kempkes, Cordula, Ikoma, Akihiko, Cevikbas, Ferda, Akiyama, Tasuku, Nunes, Frank, Seeliger, Stephan, Hasdemir, Burcu, Mess, Christian, Buhl, Timo, Sulk, Mathias, Müller, Frank-Ulrich, Metze, Dieter, Bunnett, Nigel W, Bhargava, Aditi, Carstens, Earl, Furue, Masutaka, Steinhoff, Martin
Format: Article
Language:English
Subjects:
Adult
Age
Animals
Aspartic Acid Endopeptidases - antagonists & inhibitors
Aspartic Acid Endopeptidases - genetics
Aspartic Acid Endopeptidases - metabolism
Autoimmune diseases
Biomedical research
Cellular signal transduction
Endothelin-1 - administration & dosage
Endothelin-1 - genetics
Endothelin-1 - metabolism
Endothelin-Converting Enzymes
Enzymes
Female
Ganglia, Spinal - metabolism
Health aspects
Humans
Kinases
Laboratory animals
Male
MAP Kinase Signaling System
Metalloendopeptidases - antagonists & inhibitors
Metalloendopeptidases - genetics
Metalloendopeptidases - metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Nervous system
Neurons
Neuropeptides
Pain
Physiological aspects
Proteases
Pruritus
Pruritus - etiology
Pruritus - genetics
Pruritus - metabolism
Receptor, Endothelin A - metabolism
Recycling
Signal Transduction
Skin - innervation
Skin - metabolism
Skin - pathology
Software
Up-Regulation
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Summary: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.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI67323