title: The Fabry disease-associated lipid Lyso-Gb3 enhances voltage-gated calcium currents in sensory neurons and causes pain.
abstract: Fabry disease is an X-linked lysosomal storage disorder characterised by accumulation of glycosphingolipids, and accompanied by clinical manifestations, such as cardiac disorders, renal failure, pain and peripheral neuropathy. Globotriaosylsphingosine (lyso-Gb3), a deacylated form of globotriaosylceramide (Gb3), has emerged as a marker of Fabry disease. We investigated the link between Gb3, lyso-Gb3 and pain. Plantar administration of lyso-Gb3 or Gb3 caused mechanical allodynia in healthy mice. In vitro application of 100nM lyso-Gb3 caused uptake of extracellular calcium in 10% of sensory neurons expressing nociceptor markers, rising to 40% of neurons at 1μM, a concentration that may occur in Fabry disease patients. Peak current densities of voltage-dependent Ca(2+) channels were substantially enhanced by application of 1μM lyso-Gb3. These studies suggest a direct role for lyso-Gb3 in the sensitisation of peripheral nociceptive neurons that may provide an opportunity for therapeutic intervention in the treatment of Fabry disease-associated pain.
authors.affiliation: Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, Gower St., London, WC1E 6BT, UK.
authors.forename: L
authors.initials: L
authors.lastname: Choi
authors.affiliation: Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, Gower St., London, WC1E 6BT, UK.
authors.forename: J
authors.initials: J
authors.lastname: Vernon
authors.affiliation: Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, Gower St., London, WC1E 6BT, UK.
authors.forename: O
authors.initials: O
authors.lastname: Kopach
authors.affiliation: Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, Gower St., London, WC1E 6BT, UK.
authors.forename: M S
authors.initials: MS
authors.lastname: Minett
authors.affiliation: Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, Gower St., London, WC1E 6BT, UK.
authors.forename: K
authors.initials: K
authors.lastname: Mills
authors.affiliation: Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, Gower St., London, WC1E 6BT, UK.
authors.forename: P T
authors.initials: PT
authors.lastname: Clayton
authors.affiliation: Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, Gower St., London, WC1E 6BT, UK.
authors.forename: T
authors.initials: T
authors.lastname: Meert
authors.affiliation: Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, Gower St., London, WC1E 6BT, UK; BK21 Programme, Department of Molecular Medicine, Seoul National University, South Korea. Electronic address: J.wood@ucl.ac.uk.
authors.forename: J N
authors.initials: JN
authors.lastname: Wood
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000502:physiology*; D002478:Cells, Cultured; D000795:Fabry Disease / Q000378:metabolism* / Q000503:physiopathology; D005727:Ganglia, Spinal / Q000166:cytology; D006017:Glycolipids / Q000378:metabolism / Q000494:pharmacology*; D006930:Hyperalgesia / Q000378:metabolism / Q000503:physiopathology; D008810:Mice, Inbred C57BL; D009619:Nociceptors / Q000187:drug effects* / Q000502:physiology; D010146:Pain / Q000378:metabolism* / Q000503:physiopathology; D010812:Physical Stimulation; D013107:Sphingolipids / Q000378:metabolism / Q000494:pharmacology*; D014110:Touch; D014281:Trihexosylceramides / Q000378:metabolism / Q000494:pharmacology
chemical_list: D015220:Calcium Channels; D006017:Glycolipids; D013107:Sphingolipids; D014281:Trihexosylceramides; C063288:globotriaosyl lysosphingolipid; C018549:globotriaosylceramide; D002118:Calcium
keywords: Calcium imaging; Dorsal root ganglia; Fabry disease; Pain; Voltage-dependent Ca(2+) channels