title: Small-molecule inhibition of STOML3 oligomerization reverses pathological mechanical hypersensitivity.
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.
authors.affiliation: Department of Neuroscience, Max Delbrück Center for Molecular Medicine, Berlin, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Wetzel
authors.affiliation: Department of Neuroscience, Max Delbrück Center for Molecular Medicine, Berlin, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Pifferi
authors.affiliation: Department of Neuroscience, Max Delbrück Center for Molecular Medicine, Berlin, Germany.|Department of Biomedical Sciences, Section of Cytomorphology, University of Cagliari, Monserrato (California), Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Picci
authors.affiliation: Department of Neuroscience, Max Delbrück Center for Molecular Medicine, Berlin, Germany.
authors.forename: Caglar
authors.initials: C
authors.lastname: Gök
authors.affiliation: Department of Neuroscience, Max Delbrück Center for Molecular Medicine, Berlin, Germany.|Neuroscience Research Center and Cluster of Excellence NeuroCure, Charité-Universitätsmedizin, Berlin, Germany.
authors.forename: Diana
authors.initials: D
authors.lastname: Hoffmann
authors.affiliation: Institute of Pharmacology, Heidelberg University, Heidelberg, Germany.
authors.forename: Kiran K
authors.identifier: 0000-0002-9503-1402
authors.initials: KK
authors.lastname: Bali
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie (FMP), Berlin, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Lampe
authors.affiliation: Department of Neuroscience, Max Delbrück Center for Molecular Medicine, Berlin, Germany.
authors.forename: Liudmila
authors.initials: L
authors.lastname: Lapatsina
authors.affiliation: Department of Neuroscience, Max Delbrück Center for Molecular Medicine, Berlin, Germany.
authors.forename: Raluca
authors.initials: R
authors.lastname: Fleischer
authors.affiliation: Department of Neuroscience, Max Delbrück Center for Molecular Medicine, Berlin, Germany.|Department of Pharmacology, University of Cambridge, Cambridge, UK.
authors.forename: Ewan St John
authors.identifier: 0000-0002-2699-1979
authors.initials: ES
authors.lastname: Smith
authors.affiliation: Department of Neuroscience, Max Delbrück Center for Molecular Medicine, Berlin, Germany.
authors.forename: Valérie
authors.initials: V
authors.lastname: Bégay
authors.affiliation: Department of Neuroscience, Max Delbrück Center for Molecular Medicine, Berlin, Germany.
authors.forename: Mirko
authors.initials: M
authors.lastname: Moroni
authors.affiliation: Department of Neuroscience, Max Delbrück Center for Molecular Medicine, Berlin, Germany.|Neuroscience Research Center and Cluster of Excellence NeuroCure, Charité-Universitätsmedizin, Berlin, Germany.
authors.forename: Luc
authors.initials: L
authors.lastname: Estebanez
authors.affiliation: Department of Neuroscience, Max Delbrück Center for Molecular Medicine, Berlin, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Kühnemund
authors.affiliation: Department of Neuroscience, Max Delbrück Center for Molecular Medicine, Berlin, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Walcher
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie (FMP), Berlin, Germany.
authors.forename: Edgar
authors.initials: E
authors.lastname: Specker
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie (FMP), Berlin, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Neuenschwander
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie (FMP), Berlin, Germany.
authors.forename: Jens Peter
authors.initials: JP
authors.lastname: von Kries
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie (FMP), Berlin, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Haucke
authors.affiliation: Institute of Pharmacology, Heidelberg University, Heidelberg, Germany.
authors.forename: Rohini
authors.initials: R
authors.lastname: Kuner
authors.affiliation: Department of Neuroscience, Max Delbrück Center for Molecular Medicine, Berlin, Germany.|Neuroscience Research Center and Cluster of Excellence NeuroCure, Charité-Universitätsmedizin, Berlin, Germany.
authors.forename: James F A
authors.initials: JF
authors.lastname: Poulet
authors.affiliation: Freie Universität Berlin, Berlin, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Schmoranzer
authors.affiliation: Department of Neuroscience, Max Delbrück Center for Molecular Medicine, Berlin, Germany.|Department of Physiology and EMBL Australia Node for Single Molecule Science, School of Medical Sciences, UNSW, Sydney, Australia.
authors.forename: Kate
authors.initials: K
authors.lastname: Poole
authors.affiliation: Department of Neuroscience, Max Delbrück Center for Molecular Medicine, Berlin, Germany.|Neuroscience Research Center and Cluster of Excellence NeuroCure, Charité-Universitätsmedizin, Berlin, Germany.
authors.forename: Gary R
authors.identifier: 0000-0002-2890-6352
authors.initials: GR
authors.lastname: Lewin
mesh_terms: D000818:Animals; D005727:Ganglia, Spinal / Q000378:metabolism; D006967:Hypersensitivity / Q000188:drug therapy / Q000378:metabolism*; D007473:Ion Channels / Q000378:metabolism*; D008465:Mechanoreceptors / Q000378:metabolism*; D040542:Mechanotransduction, Cellular / Q000187:drug effects / Q000502:physiology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism*; D012867:Skin / Q000294:innervation; D014110:Touch / Q000502:physiology
chemical_list: D007473:Ion Channels; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C461699:Stoml3 protein, mouse