The Fabry disease-associated lipid Lyso-Gb3 enhances voltage-gated calcium currents in sensory neurons and causes pain
| Autor: | Choi, L., Vernon, J., Kopach, O., Minett, M.S., Mills, K., Clayton, P.T., Meert, T., Wood, J.N. |
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| Rok vydání: | 2015 |
| Předmět: |
Lyso-Gb3
lyso-globotriaosylceramide Neuroscience(all) HBSS HEPES buffered saline Calcium imaging Pain PBS phosphate buffered saline Plenary Article Ganglia Spinal Physical Stimulation Animals Dorsal root ganglia Cells Cultured Sphingolipids GLA gene encoding alpha galactosidase A Trihexosylceramides Nociceptors Voltage-dependent Ca2+ channels Gb3 globotriaosylceramide respiratory system Mice Inbred C57BL nervous system Hyperalgesia Touch Fabry Disease lipids (amino acids peptides and proteins) Calcium Calcium Channels Glycolipids |
| Zdroj: | Neuroscience Letters |
| ISSN: | 0304-3940 |
| DOI: | 10.1016/j.neulet.2015.01.084 |
| Popis: | Highlights • Gb3 and Lyso-Gb3, plasma lipids accumulating in Fabry disease, cause mechanical allodynia in mice. • Lyso-Gb3 elevates intracellular calcium level in sensory neurons. • Lyso-Gb3 enhances voltage-dependent calcium currents in small-diameter DRG neurons. • Direct effects of lyso-Gb3 on sensory neurons may contribute to the pain of Fabry disease. 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 100 nM lyso-Gb3 caused uptake of extracellular calcium in 10% of sensory neurons expressing nociceptor markers, rising to 40% of neurons at 1 μM, a concentration that may occur in Fabry disease patients. Peak current densities of voltage-dependent Ca2+ channels were substantially enhanced by application of 1 μM 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. |
| Databáze: | OpenAIRE |
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