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Small-molecule inhibition of STOML3 oligomerization reverses pathological mechanical hypersensitivity.

Authors
  • Wetzel, Christiane1
  • Pifferi, Simone1
  • Picci, Cristina1, 2
  • Gök, Caglar1
  • Hoffmann, Diana1, 3
  • Bali, Kiran K4
  • Lampe, André5
  • Lapatsina, Liudmila1
  • Fleischer, Raluca1
  • Smith, Ewan St John1, 6
  • Bégay, Valérie1
  • Moroni, Mirko1
  • Estebanez, Luc1, 3
  • Kühnemund, Johannes1
  • Walcher, Jan1
  • Specker, Edgar5
  • Neuenschwander, Martin5
  • von Kries, Jens Peter5
  • Haucke, Volker5
  • Kuner, Rohini4
  • And 4 more
Type
Published Article
Journal
Nature Neuroscience
Publisher
Springer Nature
Publication Date
Feb 01, 2017
Volume
20
Issue
2
Pages
209–218
Identifiers
DOI: 10.1038/nn.4454
PMID: 27941788
Source
Medline
License
Unknown

Abstract

The skin is equipped with specialized mechanoreceptors that allow the perception of the slightest brush. Indeed, some mechanoreceptors can detect even nanometer-scale movements. Movement is transformed into electrical signals via the gating of mechanically activated ion channels at sensory endings in the skin. The sensitivity of Piezo mechanically gated ion channels is controlled by stomatin-like protein-3 (STOML3), which is required for normal mechanoreceptor function. Here we identify small-molecule inhibitors of STOML3 oligomerization that reversibly reduce the sensitivity of mechanically gated currents in sensory neurons and silence mechanoreceptors in vivo. STOML3 inhibitors in the skin also reversibly attenuate fine touch perception in normal mice. Under pathophysiological conditions following nerve injury or diabetic neuropathy, the slightest touch can produce pain, and here STOML3 inhibitors can reverse mechanical hypersensitivity. Thus, small molecules applied locally to the skin can be used to modulate touch and may represent peripherally available drugs to treat tactile-driven pain following neuropathy.

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