Activation of the L voltage-sensitive calcium channel by mitogen- activated protein (MAP) kinase following exposure of neuronal cells to β- amyloid. MAP kinase mediates β-amyloid-induced neurodegeneration

Fatma J. Ekinci, Kafait Malik, Thomas B. Shea

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Abstract

Neuronal degeneration in Alzheimer's disease (AD) has been variously attributed to increases in cytosolic calcium, reactive oxygen species, and phosphorylated forms of the microtubule-associated protein tau. β-Amyloid (βA), which accumulates extracellularly in AD brain, induces calcium influx in culture via the L voltage-sensitive calcium channel. Since this channel is normally activated by protein kinase A-mediated phosphorylation, we examined kinase activities recruited following βA treatment of cortical neurons and SH-SY-5Y neuroblastoma, βA increased channel phosphorylation; this increase was unaffected by the protein kinase A inhibitor H89 but was reduced by the mitogen-activated protein (MAP) kinase inhibitor PD98059. Pharmacological and antisense oligonucleotide-mediated reduction of MAP kinase activity also reduced βA-induced accumulation of calcium, reactive oxygen species, phospho-tau immunoreactivity, and apoptosis. These findings indicate that MAP kinase mediates multiple aspects of βA-induced neurotoxicity and indicates that calcium influx initiates neurodegeneration in AD. βA increased MAP kinase-mediated phosphorylation of membrane-associated proteins and reduced phosphorylation of cytosolic proteins without increasing overall MAP kinase activity. Increasing MAP kinase activity with epidermal growth factor did not increase channel phosphorylation. These findings indicate that redirection, rather than increased activation, of MAP kinase activity mediates βA-induced neurotoxicity.

Original languageEnglish (US)
Pages (from-to)30322-30327
Number of pages6
JournalJournal of Biological Chemistry
Volume274
Issue number42
DOIs
StatePublished - Oct 15 1999

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Calcium Channels
Mitogen-Activated Protein Kinases
Amyloid
Phosphorylation
Chemical activation
Electric potential
Calcium
Alzheimer Disease
Protein Kinase Inhibitors
Cyclic AMP-Dependent Protein Kinases
Reactive Oxygen Species
Microtubule-Associated Proteins
Antisense Oligonucleotides
Neuroblastoma
Epidermal Growth Factor
Neurons
Brain
Membrane Proteins
Phosphotransferases
Pharmacology

All Science Journal Classification (ASJC) codes

  • Biochemistry

Cite this

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title = "Activation of the L voltage-sensitive calcium channel by mitogen- activated protein (MAP) kinase following exposure of neuronal cells to β- amyloid. MAP kinase mediates β-amyloid-induced neurodegeneration",
abstract = "Neuronal degeneration in Alzheimer's disease (AD) has been variously attributed to increases in cytosolic calcium, reactive oxygen species, and phosphorylated forms of the microtubule-associated protein tau. β-Amyloid (βA), which accumulates extracellularly in AD brain, induces calcium influx in culture via the L voltage-sensitive calcium channel. Since this channel is normally activated by protein kinase A-mediated phosphorylation, we examined kinase activities recruited following βA treatment of cortical neurons and SH-SY-5Y neuroblastoma, βA increased channel phosphorylation; this increase was unaffected by the protein kinase A inhibitor H89 but was reduced by the mitogen-activated protein (MAP) kinase inhibitor PD98059. Pharmacological and antisense oligonucleotide-mediated reduction of MAP kinase activity also reduced βA-induced accumulation of calcium, reactive oxygen species, phospho-tau immunoreactivity, and apoptosis. These findings indicate that MAP kinase mediates multiple aspects of βA-induced neurotoxicity and indicates that calcium influx initiates neurodegeneration in AD. βA increased MAP kinase-mediated phosphorylation of membrane-associated proteins and reduced phosphorylation of cytosolic proteins without increasing overall MAP kinase activity. Increasing MAP kinase activity with epidermal growth factor did not increase channel phosphorylation. These findings indicate that redirection, rather than increased activation, of MAP kinase activity mediates βA-induced neurotoxicity.",
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AU - Malik, Kafait

AU - Shea, Thomas B.

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