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Loss of NR1 subunit of NMDARs in primary sensory neurons leads to hyperexcitability and pain hypersensitivity: involvement of Ca(2+)-activated small conductance potassium channels.

Publication ,  Journal Article
Pagadala, P; Park, C-K; Bang, S; Xu, Z-Z; Xie, R-G; Liu, T; Han, B-X; Tracey, WD; Wang, F; Ji, R-R
Published in: J Neurosci
August 14, 2013

It is well established that activation of NMDARs plays an essential role in spinal cord synaptic plasticity (i.e., central sensitization) and pain hypersensitivity after tissue injury. Despite prominent expression of NMDARs in DRG primary sensory neurons, the unique role of peripheral NMDARs in regulating intrinsic neuronal excitability and pain sensitivity is not well understood, in part due to the lack of selective molecular tools. To address this problem, we used Advillin-Cre driver to delete the NR1 subunit of NMDARs selectively in DRG neurons. In NR1 conditional knock-out (NR1-cKO) mice, NR1 expression is absent in DRG neurons but remains normal in spinal cord neurons; NMDA-induced currents are also eliminated in DRG neurons of these mice. Surprisingly, NR1-cKO mice displayed mechanical and thermal hypersensitivity compared with wild-type littermates. NR1-deficient DRG neurons show increased excitability, as indicated by increased frequency of action potentials, and enhanced excitatory synaptic transmission in spinal cord slices, as indicated by increased frequency of miniature EPSCs. This hyperexcitability can be reproduced by the NMDAR antagonist APV and by Ca(2+)-activated slow conductance K(+) (SK) channel blocker apamin. Furthermore, NR1-positive DRG neurons coexpress SK1/SK2 and apamin-sensitive afterhyperpolarization currents are elevated by NMDA and suppressed by APV in these neurons. Our findings reveal the hitherto unsuspected role of NMDARs in controlling the intrinsic excitability of primary sensory neurons possibly via Ca(2+)-activated SK channels. Our results also call attention to potential opposing effects of NMDAR antagonists as a treatment for pain and other neurological disorders.

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Published In

J Neurosci

DOI

EISSN

1529-2401

Publication Date

August 14, 2013

Volume

33

Issue

33

Start / End Page

13425 / 13430

Location

United States

Related Subject Headings

  • Synaptic Transmission
  • Sensory Receptor Cells
  • Reverse Transcriptase Polymerase Chain Reaction
  • Receptors, N-Methyl-D-Aspartate
  • Potassium Channels, Calcium-Activated
  • Patch-Clamp Techniques
  • Pain
  • Neurology & Neurosurgery
  • Nerve Tissue Proteins
  • Mice, Knockout
 

Citation

APA
Chicago
ICMJE
MLA
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Pagadala, P., Park, C.-K., Bang, S., Xu, Z.-Z., Xie, R.-G., Liu, T., … Ji, R.-R. (2013). Loss of NR1 subunit of NMDARs in primary sensory neurons leads to hyperexcitability and pain hypersensitivity: involvement of Ca(2+)-activated small conductance potassium channels. J Neurosci, 33(33), 13425–13430. https://doi.org/10.1523/JNEUROSCI.0454-13.2013
Pagadala, Promila, Chul-Kyu Park, Sangsu Bang, Zheng-Zhong Xu, Rou-Gang Xie, Tong Liu, Bao-Xia Han, W Daniel Tracey, Fan Wang, and Ru-Rong Ji. “Loss of NR1 subunit of NMDARs in primary sensory neurons leads to hyperexcitability and pain hypersensitivity: involvement of Ca(2+)-activated small conductance potassium channels.J Neurosci 33, no. 33 (August 14, 2013): 13425–30. https://doi.org/10.1523/JNEUROSCI.0454-13.2013.
Pagadala, Promila, et al. “Loss of NR1 subunit of NMDARs in primary sensory neurons leads to hyperexcitability and pain hypersensitivity: involvement of Ca(2+)-activated small conductance potassium channels.J Neurosci, vol. 33, no. 33, Aug. 2013, pp. 13425–30. Pubmed, doi:10.1523/JNEUROSCI.0454-13.2013.
Pagadala P, Park C-K, Bang S, Xu Z-Z, Xie R-G, Liu T, Han B-X, Tracey WD, Wang F, Ji R-R. Loss of NR1 subunit of NMDARs in primary sensory neurons leads to hyperexcitability and pain hypersensitivity: involvement of Ca(2+)-activated small conductance potassium channels. J Neurosci. 2013 Aug 14;33(33):13425–13430.

Published In

J Neurosci

DOI

EISSN

1529-2401

Publication Date

August 14, 2013

Volume

33

Issue

33

Start / End Page

13425 / 13430

Location

United States

Related Subject Headings

  • Synaptic Transmission
  • Sensory Receptor Cells
  • Reverse Transcriptase Polymerase Chain Reaction
  • Receptors, N-Methyl-D-Aspartate
  • Potassium Channels, Calcium-Activated
  • Patch-Clamp Techniques
  • Pain
  • Neurology & Neurosurgery
  • Nerve Tissue Proteins
  • Mice, Knockout