Protease nexin-1 and thrombin modulate neuronal Ca2+ homeostasis and sensitivity to glucose deprivation-induced injury

Virginia L. Smith-Swintosky, Stephen Zimmer, John W. Fenton, Mark P. Mattson

Research output: Contribution to journalArticlepeer-review

Abstract

Protease nexin-I (PN-1) is a 44 kDa serine proteinase inhibitor that rapidly inhibits thrombin by forming SDS stable complexes with serine at the catalytic site of the protease. Levels of both PN-1 and thrombin are increased in the brain in response to insults such as ischemia, suggesting roles in neural injury and repair processes. We now report that PN-1-protected cultured rat hippocampal neurons against glucose deprivation- induced damage (GDID), and the protection was abolished by equimolar thrombin. PN-1 reduced resting intracellular free calcium levels ([Ca2+],) and attenuated the elevation of [Ca2+], normally associated with GDID. Thrombin reduced neuronal survival and caused a significant increase in [Ca2+],. Submaximally toxic levels of thrombin exacerbated GDID. Calcium responses to thrombin were attenuated in neurons contacting PN-1 immunoreactive astrocytes. These findings suggest that PN-1 and thrombin play important roles in modulating neuronal calcium responses, and vulnerability, to metabolic/excitotoxic insults.

Original languageEnglish (US)
Pages (from-to)5840-5850
Number of pages11
JournalJournal of Neuroscience
Volume15
Issue number8
StatePublished - Aug 1995
Externally publishedYes

Keywords

  • Astrocytes
  • Calcium
  • Excitotoxicity
  • Fura-2
  • Glutamate
  • Hippocampus
  • Immunocytochemistry
  • Neuronal death
  • Protease nexin-1
  • Thrombin

ASJC Scopus subject areas

  • Neuroscience(all)

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