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

Hui Juan Hu; Yarimar Carrasquillo; Farzana Karim; Wonil E. Jung; Jeanne M. Nerbonne; Thomas L. Schwarz; Robert W. Gereau IV

doi:10.1016/j.neuron.2006.03.010

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

Hui Juan Hu, Yarimar Carrasquillo, Farzana Karim, Wonil E. Jung, Jeanne M. Nerbonne, Thomas L. Schwarz, Robert W. Gereau IV

Research output: Contribution to journal › Article › peer-review

210 Scopus citations

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.

Original language	English
Pages (from-to)	89-100
Number of pages	12
Journal	Neuron
Volume	50
Issue number	1
DOIs	https://doi.org/10.1016/j.neuron.2006.03.010
State	Published - Apr 6 2006

Keywords

MOLNEURO
PROTEINS
SIGNALING

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10.1016/j.neuron.2006.03.010

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title = "The Kv4.2 Potassium Channel Subunit Is Required for Pain Plasticity",

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.",

keywords = "MOLNEURO, PROTEINS, SIGNALING",

author = "Hu, {Hui Juan} and Yarimar Carrasquillo and Farzana Karim and Jung, {Wonil E.} and Nerbonne, {Jeanne M.} and Schwarz, {Thomas L.} and {Gereau IV}, {Robert W.}",

note = "Funding Information: The authors wish to thank P. Pfaffinger for generously providing the Kv4.2dn construct; and C. Qiu, S. Shalin, and B. McGill for help with mouse colony maintenance, immunostaining, and dorsal horn neuronal transfections, respectively. This work was supported by grants from the NIH (R.W.G., Y.C., J.M.N., and T.L.S.), Arthritis Foundation (F.K.), and the Paralyzed Veterans of America Spinal Cord Research Foundation (R.W.G.). ",

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AU - Hu, Hui Juan

AU - Carrasquillo, Yarimar

AU - Karim, Farzana

AU - Jung, Wonil E.

AU - Nerbonne, Jeanne M.

AU - Schwarz, Thomas L.

AU - Gereau IV, Robert W.

N1 - Funding Information: The authors wish to thank P. Pfaffinger for generously providing the Kv4.2dn construct; and C. Qiu, S. Shalin, and B. McGill for help with mouse colony maintenance, immunostaining, and dorsal horn neuronal transfections, respectively. This work was supported by grants from the NIH (R.W.G., Y.C., J.M.N., and T.L.S.), Arthritis Foundation (F.K.), and the Paralyzed Veterans of America Spinal Cord Research Foundation (R.W.G.).

PY - 2006/4/6

Y1 - 2006/4/6

N2 - 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.

AB - 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.

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

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