Calcium-dependent mitochondrial superoxide modulates nuclear CREB phosphorylation in hippocampal neurons.
We report evidence that mitochondrially produced superoxide (O(2)(-)) is involved in signaling in hippocampal neurons by examining the relationship between strong but physiological increases in cytosolic free Ca(2+), mitochondrial calcium accumulation, O(2)(-) production, and CREB phosphorylation. Strong depolarization-induced Ca(2+) entry through NMDA or L-type Ca(2+) channels evoked large Ca(2+) transients, a sustained increase in O(2)(-), and a large rise in nuclear CaM and pCREB. Under these conditions, inhibition of mitochondrial Ca(2+) uptake and consequent O(2)(-) production suppressed Ca(2+) entry-induced pCREB elevation, indicating that O(2)(-) produced by mitochondria supports CREB phosphorylation. Similarly, inhibiting mitochondrial respiration blocked O(2)(-) production and also depressed the elevation of pCREB. Blocking calcineurin reversed this depression. We conclude that strong Ca(2+) entry promotes mitochondrial calcium accumulation and the subsequent enhancement of mitochondrial O(2)(-) production, which in turn prolongs the lifetime of pCREB by suppressing calcineurin-dependent pCREB dephosphorylation.
Hongpaisan
Jarin
J
Laboratory of Neurobiology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892-4062, USA.
Winters
Christine A
CA
Andrews
S Brian
SB
D000818:Animals; D002118:Calcium / Q000502:physiology*; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013481:Superoxides / Q000494:pharmacology*
D017362:Cyclic AMP Response Element-Binding Protein; D013481:Superoxides; D002118:Calcium