Premium
Nitric oxide promotes intracellular calcium release from mitochondria in striatal neurons
Author(s) -
Horn Thomas F. W.,
Wolf Gerald,
Duffy Steven,
Weiss Samuel,
Keilhoff Gerburg,
MacVicar Brian A.
Publication year - 2002
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.02-0126com
Subject(s) - calcium , chemistry , nmda receptor , nitric oxide , ryanodine receptor , ruthenium red , thapsigargin , extracellular , calcium in biology , intracellular , biophysics , protonophore , biochemistry , mitochondrion , microbiology and biotechnology , biology , receptor , organic chemistry
Overproduction of nitric oxide by NMDA receptor stimulation is implicated in calcium deregulation and neurodegeneration of striatal neurons. We investigated the involvement of nitric oxide (NO) in inducing intracellular calcium release and in modifying calcium transients evoked by NMDA. NO application (4–10 fM) reversibly and repeatedly increased the intracellular calcium concentration [Ca 2 + ] i in Fura‐2‐or fluo‐3‐loaded cultured mouse striatal neurons. NO‐induced [Ca 2 + ] i responses persisted in the absence of extracellular calcium, indicating that Ca 2+ was released from intracellular stores. The source of calcium was distinct from [Ca 2 + ] i ‐activated (ruthenium red and ryanodine sensitive) or IP 3 ‐activated (thapsigargin‐sensitive) Ca 2+ stores and was not dependent on cGMP production because a cell permeant analog, 8‐bromo‐cGMP, did not increase basal [Ca 2 + ] i . Glucose removal potentiated the NO‐induced release of [Ca 2 + ] i . In contrast, pretreatment with either the mitochondrial uncoupler carbonyl cyanide m‐chlorophenylhydrazone or cyclosporin A, a blocker of the mitochondrial permeability transition pore, prevented the [Ca 2 + ] i increase after NO. The rise in [Ca 2 + ] i during NO exposure was preceded by a decrease in mitochondrial membrane potential that was partly reversible during washout. Repeated applications of NMDA induced irreversible [Ca 2 + ] i responses in a subpopulation of striatal cells that were greatly reduced by the NOS inhibitor N W ‐nitro‐L‐arginine. Calcium transients were prolonged by conjoint application of NMDA and NO. We conclude that NMDA‐evoked [Ca 2 + ] i transients are modulated by endogenous NO production, which leads to release of calcium from the mitochondrial pool. An NO‐activated mitochondrial permeability transition pore may lead to cell death after overstimulation of NMDA receptors.—Horn, T. F. W., Wolf, G., Duffy, S., Weiss, S., Keilhoff, G., MacVicar, B. A. Nitric oxide promotes intracellular calcium release from mitochondria in striatal neurons. FASEB J . 16, 1611–1622 (2002)