title: Neural peptidase endothelin-converting enzyme 1 regulates endothelin 1-induced pruritus.
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.forename: Makiko
authors.initials: M
authors.lastname: Kido-Nakahara
authors.forename: Jörg
authors.initials: J
authors.lastname: Buddenkotte
authors.forename: Cordula
authors.initials: C
authors.lastname: Kempkes
authors.forename: Akihiko
authors.initials: A
authors.lastname: Ikoma
authors.forename: Ferda
authors.initials: F
authors.lastname: Cevikbas
authors.forename: Tasuku
authors.initials: T
authors.lastname: Akiyama
authors.forename: Frank
authors.initials: F
authors.lastname: Nunes
authors.forename: Stephan
authors.initials: S
authors.lastname: Seeliger
authors.forename: Burcu
authors.initials: B
authors.lastname: Hasdemir
authors.forename: Christian
authors.initials: C
authors.lastname: Mess
authors.forename: Timo
authors.initials: T
authors.lastname: Buhl
authors.forename: Mathias
authors.initials: M
authors.lastname: Sulk
authors.forename: Frank-Ulrich
authors.initials: FU
authors.lastname: Müller
authors.forename: Dieter
authors.initials: D
authors.lastname: Metze
authors.forename: Nigel W
authors.initials: NW
authors.lastname: Bunnett
authors.forename: Aditi
authors.initials: A
authors.lastname: Bhargava
authors.forename: Earl
authors.initials: E
authors.lastname: Carstens
authors.forename: Masutaka
authors.initials: M
authors.lastname: Furue
authors.forename: Martin
authors.initials: M
authors.lastname: Steinhoff
mesh_terms: D000328:Adult; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019332:Endothelin-1 / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D000072396:Endothelin-Converting Enzymes; D005260:Female; D005727:Ganglia, Spinal / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011537:Pruritus / Q000209:etiology* / Q000235:genetics / Q000378:metabolism*; D044022:Receptor, Endothelin A / Q000378:metabolism; D015398:Signal Transduction; D012867:Skin / Q000294:innervation / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation
chemical_list: D019332:Endothelin-1; D044022:Receptor, Endothelin A; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; C000606923:ECE1 protein, human; C000606925:Ece1 protein, mouse; D000072396:Endothelin-Converting Enzymes