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

J Clin Invest. 2014 Jun;124(6):2683-95. doi: 10.1172/JCI67323. Epub 2014 May 8.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Aspartic Acid Endopeptidases / antagonists & inhibitors
  • Aspartic Acid Endopeptidases / genetics
  • Aspartic Acid Endopeptidases / metabolism*
  • Endothelin-1 / administration & dosage
  • Endothelin-1 / genetics
  • Endothelin-1 / metabolism*
  • Endothelin-Converting Enzymes
  • Female
  • Ganglia, Spinal / metabolism
  • Humans
  • MAP Kinase Signaling System
  • Male
  • Metalloendopeptidases / antagonists & inhibitors
  • Metalloendopeptidases / genetics
  • Metalloendopeptidases / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Pruritus / etiology*
  • Pruritus / genetics
  • Pruritus / metabolism*
  • Receptor, Endothelin A / metabolism
  • Signal Transduction
  • Skin / innervation
  • Skin / metabolism
  • Skin / pathology
  • Up-Regulation

Substances

  • Endothelin-1
  • Receptor, Endothelin A
  • Aspartic Acid Endopeptidases
  • Metalloendopeptidases
  • ECE1 protein, human
  • Ece1 protein, mouse
  • Endothelin-Converting Enzymes