Abstract
A-type potassium currents are important determinants of neuronal excitability. In spinal cord dorsal horn neurons, A-type currents are modulated by extracellular signal-regulated kinases (ERKs), which mediate central sensitization during inflammatory pain. Here, we report that Kv4.2 mediates the majority of A-type current in dorsal horn neurons and is a critical site for modulation of neuronal excitability and nociceptive behaviors. Genetic elimination of Kv4.2 reduces A-type currents and increases excitability of dorsal horn neurons, resulting in enhanced sensitivity to tactile and thermal stimuli. Furthermore, ERK-mediated modulation of excitability in dorsal horn neurons and ERK-dependent forms of pain hypersensitivity are absent in Kv4.2(-/-) mice compared to wild-type littermates. Finally, mutational analysis of Kv4.2 indicates that S616 is the functionally relevant ERK phosphorylation site for modulation of Kv4.2-mediated currents in neurons. These results show that Kv4.2 is a downstream target of ERK in spinal cord and plays a crucial role in pain plasticity.
Publication types
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Comparative Study
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Action Potentials / drug effects
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Action Potentials / physiology
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Action Potentials / radiation effects
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Analysis of Variance
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Animals
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Animals, Newborn
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Behavior, Animal / drug effects
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Behavior, Animal / physiology
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Blotting, Western / methods
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Carrageenan
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Cells, Cultured
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Constriction
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Disease Models, Animal
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Dose-Response Relationship, Radiation
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Enzyme Inhibitors / pharmacology
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Flavonoids / pharmacology
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Green Fluorescent Proteins / metabolism
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Immunohistochemistry / methods
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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, Knockout
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Motor Activity / physiology
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Mutagenesis / physiology
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Neuronal Plasticity / physiology*
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Pain / etiology
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Pain / genetics*
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Pain / physiopathology*
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Pain Measurement / methods
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Patch-Clamp Techniques / methods
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Phorbol Esters / pharmacology
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Posterior Horn Cells / physiology*
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Protein Subunits / physiology
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Reaction Time / physiology
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Reaction Time / radiation effects
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Rotarod Performance Test / methods
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Shal Potassium Channels / deficiency
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Shal Potassium Channels / physiology*
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Spinal Cord / cytology*
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Transfection / methods
Substances
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Enzyme Inhibitors
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Flavonoids
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Phorbol Esters
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Protein Subunits
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Shal Potassium Channels
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Green Fluorescent Proteins
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phorbol-12,13-diacetate
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Carrageenan
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one