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Nitric oxide (NO) signaling modulates intracellular calcium [Ca 2+ ] i and prevents alcohol‐induced neuronal death in cerebellar granule cell (CGN) cultures
Author(s) -
Kouzoukas Dimitrios Elias,
Li Guiying,
Takapoo Maysam,
Bhalla Ramesh,
Pantazis Nicholas J.
Publication year - 2008
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/fasebj.22.1_supplement.835.5
Subject(s) - chemistry , calcium , calcium in biology , soluble guanylyl cyclase , nitric oxide , microbiology and biotechnology , egta , programmed cell death , alcohol , intracellular , receptor , medicine , biochemistry , biology , apoptosis , organic chemistry , guanylate cyclase
One of alcohol's most damaging effects on the developing CNS is severe neuronal loss. For unknown reasons, the cerebellum and hippocampus are more vulnerable to alcohol‐induced neuronal loss than other regions. One possibility is that alcohol‐resistant regions have protective mechanism(s), which mitigate alcohol toxicity. Our prior studies revealed that NO is protective, reducing alcohol‐induced neuronal loss by activating a NO‐signaling pathway (NO activates guanylyl cyclase; the increase in cGMP activates cGMP‐dependent protein kinase, PKG). A current goal is to identify a downstream target for PKG. We are exploring interactions among PKG, alcohol‐induced neuronal death, and [Ca 2+ ] ¡ for several reasons. Alcohol disrupts [Ca 2+ ] ¡ homeostasis, and neurons are sensitive to calcium disruption. PKG regulates the inositol 1,4,5‐triphosphate receptor (IP 3 R), modulating [Ca 2+ ] ¡ release. Ethanol (400 mg/dl) has two effects on CGN cultures: 1) A 25% reduction in neuronal numbers; 2) A rapid (< one min) increase in [Ca 2+ ] ¡ . Calcium chelators (BAPTA‐AM; EGTA‐AM) decrease alcohol‐induced neuronal loss (<10%). An inhibitor of the IP 3 R (2‐APB) and a PKG activator (8‐Br‐cGMP) reduce both the alcohol‐induced [Ca 2+ ] ¡ surge and neuronal death (<5%). In summary, modulating [Ca 2+ ] ¡ reduces alcohol toxicity. NO may protect neurons by preventing alcohol's disruption of [Ca 2+ ] ¡ . Support: NIAAA grant AA011577