The lipid peroxidation product 4-hydroxynonenal facilitates opening of voltage-dependent Ca2+Channels in neurons by increasing protein tyrosine phosphorylation

Calcium influx through voltage-dependent calcium channels (VDCCs) mediates a variety of functions in neurons and other excitable cells, but excessive calcium influx through these channels can contribute to neuronal death in pathological settings. Oxyradical production and membrane lipid peroxidation occur in neurons in response to normal activity in neuronal circuits, whereas excessive lipid peroxidation is implicated in the pathogenesis of of neurodegenerative disorders. We now report on a specific mechanism whereby lipid peroxidation can modulate the activity of VDCCs. The lipid peroxidation product 4-hydroxy-2,3-nonenal (4HN) enhances dihydropyridine-sensitive whole-cell Ca2+ currents and increases depolarization-induced increases of intracellular Ca2+ levels in hippocampal neurons. Prolonged exposure to 4HN results in neuronal death which is prevented by treatment with glutathione an attenuated by the L-type Ca2+ channel blocker nimodipine. Tyrosine phosphorylation of alpha1 VDCC subunits is increased in neurons exposed to 4HN, and studies using inhibitors of tyrosine kinases and phosphatases indicate a requirement for tyrosine phosphorylation in the enhancement of VDCC activity in response to 4HN. Phosphorylation-mediated modulation of Ca2+ channel activity in response to lipid peroxidation may play important roles in the responses of neurons to oxidative stress in both physiological and pathological settings.