The Kv4.2 Potassium Channel Subunit Is Required for Pain Plasticity

• DOI: 10.1016/j.neuron.2006.03.010
• Publication Date: 2006-04-06T23:28:31Z
• Authors: Hui-Juan Hu; Yarimar Carrasquillo; Farzana Karim; Wonil E. Jung; Jeanne M. Nerbonne; Thomas L. Schwarz; Robert W. Gereau
• Keywords: 0301 basic medicine; PROTEINS; Neuroscience(all); Blotting, Western; Green Fluorescent Proteins; Action Potentials; Motor Activity; Carrageenan; MOLNEURO; Membrane Potentials; Mice; 03 medical and health sciences; Animals; Enzyme Inhibitors; Cells, Cultured; Flavonoids; Mice, Knockout; Analysis of Variance; Behavior, Animal; Dose-Response Relationship, Radiation; Constriction; Immunohistochemistry; Disease Models, Animal; Animals, Newborn; SIGNALING; Mutagenesis

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.