Hypoxia modulates nitric oxide-induced regulation of NMDA receptor currents and neuronal cell death.
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.
Gbadegesin
M
M
Interdisciplinary Program in Neuroscience, Georgetown University Medical Center, Washington, District of Columbia 20007, USA.
Vicini
S
S
Hewett
S J
SJ
Wink
D A
DA
Espey
M
M
Pluta
R M
RM
Colton
C A
CA
D000818:Animals; D016923:Cell Death / Q000502:physiology; D002460:Cell Line; D004553:Electric Conductivity; D018698:Glutamic Acid / Q000502:physiology; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology; D000860:Hypoxia / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008815:Mice, Inbred Strains; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D009569:Nitric Oxide / Q000494:pharmacology / Q000502:physiology*; D009589:Nitrogen Oxides; D010100:Oxygen; D010313:Partial Pressure; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism
D006834:Hydrazines; D009589:Nitrogen Oxides; C112653:PAPA NONOate; D016194:Receptors, N-Methyl-D-Aspartate; D011994:Recombinant Proteins; D009569:Nitric Oxide; D018698:Glutamic Acid; C084012:1,1-diethyl-2-hydroxy-2-nitrosohydrazine; D010100:Oxygen