Abstract
Activation of microglia by LPS leads to an induction of cytokine and NO release, reduced proliferation and increased outward K(+) conductance, the latter involving the activation of Kv1.5 and Kv1.3 channels. We studied the role of these channels for microglial function using two strategies to interfere with channel expression, a Kv1.5 knockout (Kv1.5(-/-)) mouse and an antisense oligonucleotide (AO) approach. The LPS-induced NO release was reduced by AO Kv1.5 and completely absent in the Kv1.5(-/-) animal; the AO Kv1.3 had no effect. In contrast, proliferation was augmented with both, loss of Kv1.3 or Kv1.5 channel expression. After facial nerve lesion, proliferation rate was higher in Kv1.5(-/-) animals as compared to wild type. Patch clamp experiments confirmed the reduction of the LPS-induced outward current amplitude in Kv1.5(-/-) microglia as well as in Kv1.5- or Kv1.3 AO-treated cells. Our study indicates that induction of K(+) channel expression is a prerequisite for the full functional spectrum of microglial activation.
MeSH terms
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Animals
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Brain / cytology
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Bromodeoxyuridine / metabolism
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Cell Proliferation / drug effects
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Cells, Cultured
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Chemokines / metabolism
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Cytokines / metabolism
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Dose-Response Relationship, Radiation
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Electric Stimulation / methods
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Embryo, Mammalian
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Facial Nerve Diseases / metabolism
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Facial Nerve Diseases / pathology
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Immunohistochemistry / methods
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Kv1.3 Potassium Channel / chemistry
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Kv1.3 Potassium Channel / physiology*
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Kv1.5 Potassium Channel / chemistry
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Kv1.5 Potassium Channel / genetics
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Kv1.5 Potassium Channel / physiology*
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Lipopolysaccharides / pharmacology
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Membrane Potentials / drug effects
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Membrane Potentials / physiology
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Membrane Potentials / radiation effects
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Microglia / drug effects
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Microglia / physiology*
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Nitric Oxide / metabolism
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Oligodeoxyribonucleotides, Antisense / pharmacology
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Patch-Clamp Techniques / methods
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RNA, Messenger / metabolism
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Reverse Transcriptase Polymerase Chain Reaction / methods
Substances
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Chemokines
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Cytokines
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Kv1.3 Potassium Channel
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Kv1.5 Potassium Channel
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Lipopolysaccharides
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Oligodeoxyribonucleotides, Antisense
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RNA, Messenger
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Nitric Oxide
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Bromodeoxyuridine