The kv4.2 potassium channel subunit is required for pain plasticity.
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.
Hu
Hui-Juan
HJ
Washington University Pain Center and Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Carrasquillo
Yarimar
Y
Karim
Farzana
F
Jung
Wonil E
WE
Nerbonne
Jeanne M
JM
Schwarz
Thomas L
TL
Gereau
Robert W
RW
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D015153:Blotting, Western / Q000379:methods; D002351:Carrageenan; D002478:Cells, Cultured; D003250:Constriction; D004195:Disease Models, Animal; D004307:Dose-Response Relationship, Radiation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology; D016296:Mutagenesis / Q000502:physiology; D009473:Neuronal Plasticity / Q000502:physiology*; D010146:Pain / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology*; D010147:Pain Measurement / Q000379:methods; D018408:Patch-Clamp Techniques / Q000379:methods; D010703:Phorbol Esters / Q000494:pharmacology; D020671:Posterior Horn Cells / Q000502:physiology*; D021122:Protein Subunits / Q000502:physiology; D011930:Reaction Time / Q000502:physiology / Q000528:radiation effects; D045442:Rotarod Performance Test / Q000379:methods; D051672:Shal Potassium Channels / Q000172:deficiency / Q000502:physiology*; D013116:Spinal Cord / Q000166:cytology*; D014162:Transfection / Q000379:methods
D004791:Enzyme Inhibitors; D005419:Flavonoids; D010703:Phorbol Esters; D021122:Protein Subunits; D051672:Shal Potassium Channels; D049452:Green Fluorescent Proteins; C008874:phorbol-12,13-diacetate; D002351:Carrageenan; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one