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The Journal of Neuroscience, July 26, 2006, 26(30):7984-7994; doi:10.1523/JNEUROSCI.2211-06.2006

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Cellular/Molecular
Sodium Channel 2 Subunits Regulate Tetrodotoxin-Sensitive Sodium Channels in Small Dorsal Root Ganglion Neurons and Modulate the Response to Pain

Luis F. Lopez-Santiago,¹ Marie Pertin,^2,3 Xavier Morisod,^2,3 Chunling Chen,¹ Shuangsong Hong,⁴ John Wiley,⁴ Isabelle Decosterd,^2,3 * and Lori L. Isom^1 *

¹Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109-0632, ²Anesthesiology Pain Research Group, Anesthesiology Department, Lausanne University Hospital (Centre Hospitalier Universitaire Vaudois), CH-1011 Lausanne, Switzerland, ³Department of Cell Biology and Morphology, Faculty of Biology and Medicine, University of Lausanne, CH-1005 Lausanne, Switzerland, and ⁴Department of Internal Medicine and General Clinical Research Center, University of Michigan, Ann Arbor, Michigan 48109-0108

Correspondence should be addressed to Dr. Lori L. Isom, Department of Pharmacology, University of Michigan, 1301 MSRB III, 1150 West Medical Center Drive, Ann Arbor, MI 48109-0632. lisom{at}umich.edu

Voltage-gated sodium channel (Na_v1) 2 subunits modulate channel gating, assembly, and cell-surface expression in CNS neurons in vitro and in vivo. 2 expression increases in sensory neurons after nerve injury, and development of mechanical allodynia in the spared nerve injury model is attenuated in 2-null mice. Thus, we hypothesized that 2 modulates electrical excitability in dorsal root ganglion (DRG) neurons in vivo. We compared sodium currents (I_Na) in small DRG neurons from 2^+/+ and 2^–/– mice to determine the effects of 2 on tetrodotoxin-sensitive (TTX-S) and tetrodotoxin-resistant (TTX-R) Na_v1 in vivo. Small-fast DRG neurons acutely isolated from 2^–/– mice showed significant decreases in TTX-S I_Na compared with 2^+/+ neurons. This decrease included a 51% reduction in maximal sodium conductance with no detectable changes in the voltage dependence of activation or inactivation. TTX-S, but not TTX-R, I_Na activation and inactivation kinetics in these cells were slower in 2^–/– mice compared with controls. The selective regulation of TTX-S I_Na was supported by reductions in transcript and protein levels of TTX-S Na_v1s, particularly Na_v1.7. Low-threshold mechanical sensitivity was preserved in 2^–/– mice, but they were more sensitive to noxious thermal stimuli than wild type whereas their response during the late phase of the formalin test was attenuated. Our results suggest that 2 modulates TTX-S Na_v1 mRNA and protein expression resulting in increased TTX-S I_Na and increases the rates of TTX-S Na_v1 activation and inactivation in small-fast DRG neurons in vivo. TTX-R I_Na were not significantly modulated by 2.

Key words: sodium channel; subunit; dorsal root ganglion; tetrodotoxin sensitive; nociception; mouse

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Received Jan. 26, 2006; revised June 20, 2006; accepted June 21, 2006.

Correspondence should be addressed to Dr. Lori L. Isom, Department of Pharmacology, University of Michigan, 1301 MSRB III, 1150 West Medical Center Drive, Ann Arbor, MI 48109-0632. lisom{at}umich.edu

This article has been cited by other articles:

				W. J. Brackenbury, T. H. Davis, C. Chen, E. A. Slat, M. J. Detrow, T. L. Dickendesher, B. Ranscht, and L. L. Isom Voltage-Gated Na+ Channel {beta}1 Subunit-Mediated Neurite Outgrowth Requires Fyn Kinase and Contributes to Postnatal CNS Development In Vivo J. Neurosci., March 19, 2008; 28(12): 3246 - 3256. [Abstract] [Full Text] [PDF]

				A. M. Rush, T. R. Cummins, and S. G. Waxman Multiple sodium channels and their roles in electrogenesis within dorsal root ganglion neurons J. Physiol., February 15, 2007; 579(1): 1 - 14. [Abstract] [Full Text] [PDF]

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