Excessive Na+/H+ exchange in disruption of dendritic Na+and Ca2+ homeostasis and mitochondrial dysfunction following in vitro ischemia

Douglas B. Kintner, Xinzhi Chen, Julia Currie, Vishal Chanana, Peter Ferrazzano, Akemichi Baba, Toshio Matsuda, Mike Cohen, John Orlowski, Shing Yan Chiu, Jack Taunton, Dandan Sun

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Abstract

Neuronal dendrites are vulnerable to injury under diverse pathological conditions. However, the underlying mechanisms for dendritic Na+ overload and the selective dendritic injury remain poorly understood. Our current study demonstrates that activation of NHE-1 (Na+/H + exchanger isoform 1) in dendrites presents a major pathway for Na+ overload. Neuronal dendrites exhibited higher pHi regulation rates than soma as a result of a larger surface area/volume ratio. Following a 2-h oxygen glucose deprivation and a 1-h reoxygenation, NHE-1 activity was increased by ∼70-200% in dendrites. This elevation depended on activation of p90 ribosomal S6 kinase. Moreover, stimulation of NHE-1 caused dendritic Na+i accumulation, swelling, and a concurrent loss of Ca2+i homeostasis. The Ca2+i overload in dendrites preceded the changes in soma. Inhibition of NHE-1 or the reverse mode of Na+/Ca2+ exchange prevented these changes. Mitochondrial membrane potential in dendrites depolarized 40 min earlier than soma following oxygen glucose deprivation/ reoxygenation. Blocking NHE-1 activity not only attenuated loss of dendritic mitochondrial membrane potential and mitochondrial Ca2+ homeostasis but also preserved dendritic membrane integrity. Taken together, our study demonstrates that NHE-1-mediated Na+ entry and subsequent Na+/Ca2+ exchange activation contribute to the selective dendritic vulnerability to in vitro ischemia.

Original languageEnglish (US)
Pages (from-to)35155-35168
Number of pages14
JournalJournal of Biological Chemistry
Volume285
Issue number45
DOIs
StatePublished - Nov 5 2010

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Kintner, D. B., Chen, X., Currie, J., Chanana, V., Ferrazzano, P., Baba, A., Matsuda, T., Cohen, M., Orlowski, J., Chiu, S. Y., Taunton, J., & Sun, D. (2010). Excessive Na+/H+ exchange in disruption of dendritic Na+and Ca2+ homeostasis and mitochondrial dysfunction following in vitro ischemia. Journal of Biological Chemistry, 285(45), 35155-35168. https://doi.org/10.1074/jbc.M110.101212