title: P2X7 purinoceptor alterations in dystrophic mdx mouse muscles: relationship to pathology and potential target for treatment.
abstract: Duchenne muscular dystrophy (DMD) is a lethal inherited muscle disorder. Pathological characteristics of DMD skeletal muscles include, among others, abnormal Ca(2+)  homeostasis and cell signalling. Here, in the mdx mouse model of DMD, we demonstrate significant P2X7 receptor abnormalities in isolated primary muscle cells and cell lines and in dystrophic muscles in vivo. P2X7 mRNA expression in dystrophic muscles was significantly up-regulated but without alterations of specific splice variant patterns. P2X7 protein was also up-regulated and this was associated with altered function of P2X7 receptors producing increased responsiveness of cytoplasmic Ca(2+)  and extracellular signal-regulated kinase (ERK) phosphorylation to purinergic stimulation and altered sensitivity to NAD. Ca(2+)  influx and ERK signalling were stimulated by ATP and BzATP, inhibited by specific P2X7 antagonists and insensitive to ivermectin, confirming P2X7 receptor involvement. Despite the presence of pannexin-1, prolonged P2X7 activation did not trigger cell permeabilization to propidium iodide or Lucifer yellow. In dystrophic mice, in vivo treatment with the P2X7 antagonist Coomassie Brilliant Blue reduced the number of degeneration-regeneration cycles in mdx skeletal muscles. Altered P2X7 expression and function is thus an important feature in dystrophic mdx muscle and treatments aiming to inhibit P2X7 receptor might slow the progression of this disease.
authors.affiliation: School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, UK.
authors.forename: Christopher N J
authors.initials: CN
authors.lastname: Young
authors.forename: Wojciech
authors.initials: W
authors.lastname: Brutkowski
authors.forename: Chun-Fu
authors.initials: CF
authors.lastname: Lien
authors.forename: Stephen
authors.initials: S
authors.lastname: Arkle
authors.forename: Hanns
authors.initials: H
authors.lastname: Lochmüller
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Zabłocki
authors.forename: Dariusz C
authors.initials: DC
authors.lastname: Górecki
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000502:physiology; D002460:Cell Line; D017630:Connexins / Q000032:analysis; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D006801:Humans; D007559:Ivermectin / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018482:Muscle, Skeletal / Q000187:drug effects; D009137:Muscular Dystrophy, Animal / Q000378:metabolism / Q000503:physiopathology*; D009419:Nerve Tissue Proteins / Q000032:analysis; D010766:Phosphorylation / Q000502:physiology; D020033:Protein Isoforms / Q000502:physiology*; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology; D058486:Receptors, Purinergic P2X7 / Q000096:biosynthesis / Q000502:physiology*; D015854:Up-Regulation
chemical_list: D017630:Connexins; D009419:Nerve Tissue Proteins; C503631:Panx1 protein, mouse; D020033:Protein Isoforms; D058920:Purinergic P2X Receptor Antagonists; D058486:Receptors, Purinergic P2X7; D007559:Ivermectin; D000255:Adenosine Triphosphate; D048049:Extracellular Signal-Regulated MAP Kinases; D002118:Calcium