title: Peroxynitrite mediates disruption of Ca2+ homeostasis by carbon monoxide via Ca2+ ATPase degradation.
abstract: OBJECTIVE
  Sublethal carbon monoxide poisoning causes prolonged neurological damage involving oxidative stress. Given the central role of Ca(2+) homeostasis and its vulnerability to stress, we investigated whether CO disrupts neuronal Ca(2+) homeostasis.
  
  
  RESULTS
  Cytosolic Ca(2+) transients evoked by muscarine in SH-SY5Y cells were prolonged by CO (applied via the donor CORM-2), and capacitative Ca(2+) entry (CCE) was dramatically enhanced. Ca(2+) store mobilization by cyclopiazonic acid was similarly augmented, as was the subsequent CCE, and that evoked by thapsigargin. Ca(2+) rises evoked by depolarization were also enhanced by CO, and Ca(2+) levels often did not recover in its presence. CO increased intracellular nitric oxide (NO) and all effects of CO were prevented by inhibiting NO formation. However, NO donors did not mimic the effects of CO. The antioxidant ascorbic acid inhibited effects of CO on Ca(2+) signaling, as did the peroxynitrite scavenger, FeTPPS, and CO increased peroxynitrite formation. Finally, CO caused significant loss of plasma membrane Ca(2+)ATPase (PMCA) protein, detected by Western blot, and this was also observed in brain tissue of rats exposed to CO in vivo.
  
  
  METHODS
  The cellular basis of CO-induced neurotoxicity is currently unknown. Our findings provide the first data to suggest signaling pathways through which CO causes neurological damage, thereby opening up potential targets for therapeutic intervention.
  
  
  CONCLUSIONS
  CO stimulates formation of NO and reactive oxygen species which, via peroxynitrite formation, inhibit Ca(2+) extrusion via PMCA, leading to disruption of Ca(2+) signaling. We propose this contributes to the neurological damage associated with CO toxicity.
authors.affiliation: Leeds Institute of Genetics, Health & Therapeutics, Faculties of Medicine and Health, University of Leeds, United Kingdom.
authors.forename: Nishani T
authors.initials: NT
authors.lastname: Hettiarachchi
authors.forename: John P
authors.initials: JP
authors.lastname: Boyle
authors.forename: Claudia C
authors.initials: CC
authors.lastname: Bauer
authors.forename: Mark L
authors.initials: ML
authors.lastname: Dallas
authors.forename: Hugh A
authors.initials: HA
authors.lastname: Pearson
authors.forename: Shuichi
authors.initials: S
authors.lastname: Hara
authors.forename: Nikita
authors.initials: N
authors.lastname: Gamper
authors.forename: Chris
authors.initials: C
authors.lastname: Peers
mesh_terms: D002118:Calcium / Q000378:metabolism*; D000252:Calcium-Transporting ATPases / Q000378:metabolism*; D002248:Carbon Monoxide / Q000494:pharmacology*; D002460:Cell Line; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D006868:Hydrolysis; D030421:Peroxynitrous Acid / Q000494:pharmacology*
chemical_list: D030421:Peroxynitrous Acid; D002248:Carbon Monoxide; D000252:Calcium-Transporting ATPases; D002118:Calcium