Specific vulnerability of mouse spinal cord motoneurons to membrane depolarization

Myriam Gou-Fabregas, Ana Garcera, Stefka Mincheva, M. Jose Perez-Garcia, Joan X. Comella, Rosa M. Soler

Research output: Contribution to journalArticleResearchpeer-review

18 Citations (Scopus)

Abstract

Intracellular calcium (Ca2+) concentration determines neuronal dependence on neurotrophic factors (NTFs) and susceptibility to cell death. Ca2+ overload induces neuronal death and the consequences are thought to be a probable cause of motoneuron (MN) degeneration in neurodegenerative diseases. In the present study, we show that membrane depolarization with elevated extracellular potassium (K+) was toxic to cultured embryonic mouse spinal cord MNs even in the presence of NTFs. Membrane depolarization induced an intracellular Ca2+ increase. Depolarization-induced toxicity and increased intracellular Ca2+ were blocked by treatment with antagonists to some of the voltage-gated Ca2+ channels (VGCCs), indicating that Ca2+ influx through these channels contributed to the toxic effect of depolarization. Ca2+ activates the calpains, cysteine proteases that degrade a variety of substrates, causing cell death. We investigated the functional involvement of calpain using a calpain inhibitor and calpain gene silencing. Pre-treatment of MNs with calpeptin (a cell-permeable calpain inhibitor) rescued MNs survival; calpain RNA interference had the same protective effect, indicating that endogenous calpain contributes to the cell death caused by membrane depolarization. These findings suggest that MNs are especially vulnerable to extracellular K+ concentration, which induces cell death by causing both intracellular Ca2+ increase and calpain activation. © 2009 International Society for Neurochemistry.
Original languageEnglish
Pages (from-to)1842-1854
JournalJournal of Neurochemistry
Volume110
DOIs
Publication statusPublished - 1 Jan 2009

Keywords

  • Calpain
  • Intracellular calcium
  • Membrane depolarization
  • Motoneuron
  • Neuronal survival

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