Molecular Medicine

, Volume 13, Issue 7–8, pp 356–361 | Cite as

Mild Acidosis Enhances AMPA Receptor-Mediated Intracellular Zinc Mobilization in Cortical Neurons

  • Valerio Frazzini
  • Ilario G. Rapposelli
  • Carlo Corona
  • Erica Rockabrand
  • Lorella M. T. Canzoniero
  • Stefano L. Sensi


Overactivation of glutamate receptors and subsequent deregulation of the intraneuronal calcium ([Ca2+]i) levels are critical components of the injurious pathways initiated by cerebral ischemia. Another hallmark of stroke is parenchymal acidosis, and we have previously shown that mild acidosis can act as a switch to decrease NMDAR-dependent neuronal loss while potentiating the neuronal loss mediated by AMPARs. Potentiation of AMPAR-mediated neuronal death in an acidotic environment was originally associated only with [Ca2+]i dyshomeostasis, as assessed by Ca2+ imaging; however, intracellular dyshomeostasis of another divalent cation, Zn2+, has recently emerged as another important co-factor in ischemic neuronal injury. Rises in [Zn2+]i greatly contribute to the fluorescent changes of Ca2+-sensitive fluorescent probes, which also have great affinity for Zn2+. We therefore revisited our original findings (Mcdonald et al., 1998) and investigated if AMPAR-mediated fura-2 signals we observed could also be partially due to [Zn2+]i increases. Fura-2 loaded neuronal cultures were exposed to the AMPAR agonist, kainate, in a physiological buffer at pH 7.4 and then washed either at pH 7.4 or pH 6.2. A delayed recovery of fura-2 signals was observed at both pHs. Interestingly this impaired recovery phase was found to be sensitive to chelation of intracellular Zn2+. Experiments with the Zn2+ sensitive (and Ca2+-insensitive) fluorescent probe FluoZin-3 confirmed the idea that AMPAR activation increases [Zn2+]i, a phenomenon that is potentiated by mild acidosis. Additionally, our results show that selective Ca2+ imaging mandates the use of intracellular heavy metal chelators to avoid confounding effects of endogenous metals such as Zn2+.



We thank Tiziana D’Ettorre and Francesca Faricelli for expert assistance with cell cultures. This work was supported by PRIN 2004, FIRB 2003, and PRIN 2006 (SLS).


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Copyright information

© Feinstein Institute for Medical Research 2007

Authors and Affiliations

  • Valerio Frazzini
    • 1
  • Ilario G. Rapposelli
    • 1
  • Carlo Corona
    • 1
  • Erica Rockabrand
    • 1
  • Lorella M. T. Canzoniero
    • 4
  • Stefano L. Sensi
    • 1
    • 2
    • 3
  1. 1.Department of Basic and Applied Medical Science, Molecular Neurology Unit, CeSI-Center for Excellence on AgingUniversity ‘G. d’Annunzio’ChietiItaly
  2. 2.Department of NeurologyUniversity of CaliforniaIrvine, IrvineUSA
  3. 3.Department of NeurologyUniversity of Texas Medical BranchGalveston, GalvestonUSA
  4. 4.Department of Biology and Environmental SciencesUniversity of SannioBeneventoItaly

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