Pannexin 1 involvement in bladder dysfunction in a multiple sclerosis model

Sci Rep. 2013;3:2152. doi: 10.1038/srep02152.

Abstract

Bladder dysfunction is common in Multiple Sclerosis (MS) but little is known of its pathophysiology. We show that mice with experimental autoimmune encephalomyelitis (EAE), a MS model, have micturition dysfunction and altered expression of genes associated with bladder mechanosensory, transduction and signaling systems including pannexin 1 (Panx1) and Gja1 (encoding connexin43, referred to here as Cx43). EAE mice with Panx1 depletion (Panx1(-/-)) displayed similar neurological deficits but lesser micturition dysfunction compared to Panx1(+/+) EAE. Cx43 and IL-1β upregulation in Panx1(+/+) EAE bladder mucosa was not observed in Panx1(-/-) EAE. In urothelial cells, IL-1β stimulation increased Cx43 expression, dye-coupling, and p38 MAPK phosphorylation but not ERK1/2 phosphorylation. SB203580 (p38 MAPK inhibitor) prevented IL-1β-induced Cx43 upregulation. IL-1β also increased IL-1β, IL-1R-1, PANX1 and CASP1 expression. Mefloquine (Panx1 blocker) reduced these IL-1β responses. We propose that Panx1 signaling provides a positive feedback loop for inflammatory responses involved in bladder dysfunction in MS.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Connexin 43 / genetics
  • Connexins / genetics
  • Connexins / physiology*
  • Disease Models, Animal
  • Encephalomyelitis, Autoimmune, Experimental / physiopathology*
  • Interleukin-1beta / genetics
  • Mice
  • Multiple Sclerosis / physiopathology*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / physiology*
  • Phosphorylation
  • Protein Kinases / metabolism
  • Signal Transduction
  • Urinary Bladder / physiopathology*

Substances

  • Connexin 43
  • Connexins
  • Interleukin-1beta
  • Nerve Tissue Proteins
  • Panx1 protein, mouse
  • Protein Kinases