Nitric oxide disrupts Ca2+ homeostasis in hippocampal neurons.
Nitric oxide has been recognized in recent years as an important mediator of neuronal toxicity, which in many cases involves alterations of the cytoplasmic Ca2+ concentration ([Ca2+]i). In [Ca2+]i fluorimetric experiments on cultured hippocampal neurons, the nitric oxide-releasing agent S-nitrosocysteine produced a delayed rise in [Ca2+]i over a 20-min exposure, which was accompanied by a progressive slowing of the kinetics of recovery from depolarization-induced [Ca2+]i transients. These effects were blocked by oxyhemoglobin and by superoxide dismutase, confirming nitric oxide as the responsible agent, and suggesting that they involved peroxynitrite formation. Similar alterations of [Ca2+]i homeostasis were produced by the mitochondrial ATP synthase inhibitor oligomycin, and when an ATP-regenerating system was supplied via the patch pipette in combined whole-cell patch-clamp-[Ca2+]i fluorimetry experiments, S-nitrosocysteine had no effect on the resting [Ca2+]i or on the recovery kinetics of [Ca2+]i transients induced by direct depolarization. We conclude that prolonged exposure to nitric oxide disrupts [Ca2+]i homeostasis in hippocampal neurons by impairing Ca2+ removal from the cytoplasm, possibly as a result of ATP depletion. The resulting persistent alterations in [Ca2+]i may contribute to the delayed neurotoxicity of nitric oxide.
Brorson
J R
JR
Department of Neurology, University of Chicago, Illinois 60637, USA.
Sulit
R A
RA
Zhang
H
H
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D003545:Cysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D003593:Cytoplasm / Q000378:metabolism; D005470:Fluorometry; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000378:metabolism*; D009569:Nitric Oxide / Q000502:physiology*; D009994:Osmolar Concentration; D018408:Patch-Clamp Techniques; D051381:Rats / Q000196:embryology; D011919:Rats, Inbred Strains; D026403:S-Nitrosothiols
D026403:S-Nitrosothiols; D009569:Nitric Oxide; C021315:S-nitrosocysteine; D003545:Cysteine; D002118:Calcium