The actin-severing protein gelsolin modulates calcium channel and NMDA receptor activities and vulnerability to excitotoxicity in hippocampal neurons

Katsutoshi Furukawa, Weiming Fu, Ying Li, Walter Witke, David J. Kwiatkowski, Mark P. Mattson

Research output: Contribution to journalArticle

Abstract

Calcium influx through NMDA receptors and voltage-dependent calcium channels (VDCC) mediates an array of physiological processes in neurons and may also contribute to neuronal degeneration and death in neurodegenerative conditions such as stroke and severe epileptic seizures. Gelsolin is a Ca2+-activated actin-severing protein that is expressed in neurons, wherein it may mediate motility responses to Ca2+ influx. Primary hippocampal neurons cultured from mice lacking gelsolin exhibited decreased actin filament depolymerization and enhanced Ca2+ influx after exposure to glutamate. Whole-cell patch-clamp analyses showed that currents through NMDA receptors and VDCC were enhanced in hippocampal neurons lacking gelsolin, as a result of decreased current rundown; kainate-induced currents were similar in neurons containing and lacking gelsolin. Vulnerability of cultured hippocampal neurons to glutamate toxicity was greater in cells lacking gelsolin. Seizure-induced damage to hippocampal pyramidal neurons was exacerbated in adult gelsolin-deficient mice. These findings identify novel roles for gelsolin in controlling actin-mediated feedback regulation of Ca2+ influx and in neuronal injury responses. The data further suggest roles for gelsolin and the actin cytoskeleton in both physiological and pathophysiological events that involve activation of NMDA receptors and VDCC.

Original languageEnglish (US)
Pages (from-to)8178-8186
Number of pages9
JournalJournal of Neuroscience
Volume17
Issue number21
StatePublished - 1997
Externally publishedYes

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Keywords

  • Cytochalasin
  • Cytoskeleton
  • Epileptic seizures
  • Fura-2
  • Knock-out mice
  • Patch-clamp

ASJC Scopus subject areas

  • Neuroscience(all)

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