Hypoxia modulates nitric oxide-induced regulation of NMDA receptor currents and neuronal cell death

Muyiwa Gbadegesin, Stefano Vicini, Sandra Hewett, David A. Wink, Michael Espey, Ryszard M. Pluta, Carol A. Colton

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40 Scopus citations

Abstract

Nitric oxide (NO) released from a new chemical class of donors enhances N-methyl-D-aspartate (NMDA) channel activity. Using whole cell and single- channel patch-clamp techniques, we have shown that (Z)-1-[N(3-ammoniopropyl)- N-(n-propyl)amino]-NO (PAPA-NO) and diethylamine NO, commonly termed NONOates, potentiate the glutamate-mediated response of recombinant rat NMDA receptors(NR1/NR2A) expressed in HEK-293 cells. The overall effect is an increase in both peak and steady-state whole cell currents induced by glutamate. Single-channel studies demonstrate a significant increase in open probability but no change in the mean single-channel open time or mean channel conductance. Reduction in oxygen levels increased and prolonged the PAPA-NO-induced change in both peak and steady-state glutamate currents in transfected HEK cells. PAPA-NO also enhanced cell death in primary cultures of rodent cortical neurons deprived of oxygen and glucose. This potentiation of neuronal injury was blocked by MK-801, indicating a critical involvement of NMDA receptor activation. The NO-induced increase in NMDA channel activity as well as NMDA receptor-mediated cell death provide firm evidence that NO modulates the NMDA channel in a manner consistent with both a physiological role under normoxic conditions and a pathophysiological role under hypoxic conditions.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Cell Physiology
Volume277
Issue number4 46-4
StatePublished - 1999
Externally publishedYes

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Keywords

  • N-methyl-D-aspartate
  • Oxygen-glucose deprivation
  • PAPA-NO

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Cell Biology
  • Physiology
  • Physiology (medical)

Cite this

Gbadegesin, M., Vicini, S., Hewett, S., Wink, D. A., Espey, M., Pluta, R. M., & Colton, C. A. (1999). Hypoxia modulates nitric oxide-induced regulation of NMDA receptor currents and neuronal cell death. American Journal of Physiology - Cell Physiology, 277(4 46-4).