The Lipid Peroxidation Product 4-Hydroxynonenal Facilitates Opening of Voltage-dependent Ca2+ Channels in Neurons by Increasing Protein Tyrosine Phosphorylation

Abstract

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 Ca 2؉ currents and increases depolarization-induced increases of intracellular Ca 2؉ levels in hippocampal neurons. Prolonged exposure to 4HN results in neuronal death, which is prevented by treatment with glutathione and attenuated by the L-type Ca 2؉ channel blocker nimodipine. Tyrosine phosphorylation of ␣1 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 Ca 2؉ 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.

Baroreflex function in conscious rats submitted to iron overload

“…In addition, myocardial Fe 2+ uptake has been reported to occur via L-type Ca 2+ channels (29), indicating a complex interaction between calcium, iron and free radical generation in the heart and neuronal tissue. In synthesis, both excess of iron and free radicals have been implicated in the disruption of intracellular calcium homeostasis (32,33) not only in cardiomyocytes but also in neurons (34,35). Taken together, these reports agree with the hypothesis that the increase in baroreflex tachycardia (Figure 3) could represent an adjustment process to compensate for iron-induced failure in myocardial function, sustaining, at least in part, blood pressure within normal levels.…”

The chemistry of cell signaling by reactive oxygen and nitrogen species and 4-hydroxynonenal

“…Lu et al recently reported that 2 h after exposure to 1-10 μM HNE Ca 2+ current was increased by 40% in hippocampal neurons, and the cytosolic Ca 2+ level was increased to about 400 nM. Further study showed that HNE activated voltage-dependent Ca 2+ channel (VDCC) through tyrosine kinasemediated phosphorylation instead of direct conjugation to VDCC (226). The HNE activation of VDCC was further confirmed by Akaishi et al, who found that 10 μM HNE stimulated VDCC in dentate granule cells (227).…”

Calcium dysregulation in Alzheimer's disease: Recent advances gained from genetically modified animals

“…In addition, when cultured neurons are incubated with A␤, both ROS and HNE levels increase [71]. HNE has been shown to specifically enhance L-type VGCC currents through a mechanism involving increased tyrosine phosphorylation [72]. In addition Peers and colleagues have demonstrated that A␤ can act post-transcriptionally to promote the L-type ␣1C subunit insertion (or stabilization) into the plasma membrane [73].…”