The Fabry disease-associated lipid Lyso-Gb3 enhances voltage-gated calcium currents in sensory neurons and causes pain. (6th May 2015)

• Record Type: Journal Article
• Authors: Choi, L.; Vernon, J.; Kopach, O.; Minett, M.S.; Mills, K.; Clayton, P.T.; Meert, T.; Wood, J.N.
• Is Part Of: Neuroscience letters. Volume 594(2015)
• Page Start: 163
• Page End: 168
• Publication Date: 2015-05-06
• Subjects: Gb3 globotriaosylceramide -- Lyso-Gb3 lyso-globotriaosylceramide -- GLA gene encoding alpha galactosidase A -- HBSS HEPES buffered saline -- PBS phosphate buffered saline; Pain -- Calcium imaging -- Voltage-dependent Ca2+ channels -- Fabry disease -- Dorsal root ganglia; Neurology -- Periodicals; Neurology -- Periodicals; Research -- Periodicals; Neurologie -- Périodiques; Neuroanatomie -- Périodiques; Neuropharmacologie -- Périodiques; Neurophysiologie -- Périodiques; Neurology; Periodicals; Electronic journals; 617.48
• DOI: 10.1016/j.neulet.2015.01.084
• Languages: English
• ISSNs: 0304-3940

Abstract

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. 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 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 Ca 2+ 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.