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Small-molecule inhibition of STOML3 oligomerization reverses pathological mechanical hypersensitivity

Item Type:Article
Title:Small-molecule inhibition of STOML3 oligomerization reverses pathological mechanical hypersensitivity
Creators Name:Wetzel, C. and Pifferi, S. and Picci, C. and Gök, C. and Hoffmann, D. and Bali, K.K. and Lampe, A. and Lapatsina, L. and Fleischer, R. and Smith, E.S.J. and Bégay, V. and Moroni, M. and Estebanez, L. and Kühnemund, J. and Walcher, J. and Specker, E. and Neuenschwander, M. and von Kries, J.P. and Haucke, V. and Kuner, R. and Poulet, J.F.A. and Schmoranzer, J. and Poole, K. and Lewin, G.R.
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.
Keywords:Cellular Mechanotransduction, Hypersensitivity, Inbred C57BL Mice, Ion Channels, Mechanoreceptors, Membrane Proteins, Nerve Tissue Proteins, Sensory Receptor Cells, Skin, Spinal Ganglia, Touch, Transgenic Mice, Animals, Mice
Source:Nature Neuroscience
ISSN:1097-6256
Publisher:Nature Publishing Group (U.S.A.)
Volume:20
Number:2
Page Range:209-218
Date:February 2017
Official Publication:https://doi.org/10.1038/nn.4454
PubMed:View item in PubMed

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