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Reduced Sodium Channel Density, Altered Voltage Dependence of Inactivation, and Increased Susceptibility to Seizures in Mice Lacking Sodium Channel Beta 2-Subunits

Citation

Chen, Chunling; Bharucha, Vandana; Chen, Yuan; Westenbroek, Ruth E.; Brown, Angus; Malhotra, Jyoti Dhar; Jones, Dorothy; Avery, Christy L.; Gillespie, Patrick J., III; & Kazen-Gillespie, Kristin A., et al. (2002). Reduced Sodium Channel Density, Altered Voltage Dependence of Inactivation, and Increased Susceptibility to Seizures in Mice Lacking Sodium Channel Beta 2-Subunits. Proceedings of the National Academy of Sciences of the United States of America, 99(26), 17072-7. PMCID: PMC139271

Abstract

Sodium channel beta-subunits modulate channel gating, assembly, and cell surface expression in heterologous cell systems. We generated beta2(-/-) mice to investigate the role of beta2 in control of sodium channel density, localization, and function in neurons in vivo. Measurements of [(3)H]saxitoxin (STX) binding showed a significant reduction in the level of plasma membrane sodium channels in beta2(-/-) neurons. The loss of beta2 resulted in negative shifts in the voltage dependence of inactivation as well as significant decreases in sodium current density in acutely dissociated hippocampal neurons. The integral of the compound action potential in optic nerve was significantly reduced, and the threshold for action potential generation was increased, indicating a reduction in the level of functional plasma membrane sodium channels. In contrast, the conduction velocity, the number and size of axons in the optic nerve, and the specific localization of Na(v)1.6 channels in the nodes of Ranvier were unchanged. beta2(-/-) mice displayed increased susceptibility to seizures, as indicated by reduced latency and threshold for pilocarpine-induced seizures, but seemed normal in other neurological tests. Our observations show that beta2-subunits play an important role in the regulation of sodium channel density and function in neurons in vivo and are required for normal action potential generation and control of excitability.

URL

http://dx.doi.org/10.1073/pnas.212638099

Reference Type

Journal Article

Journal Title

Proceedings of the National Academy of Sciences of the United States of America

Author(s)

Chen, Chunling
Bharucha, Vandana
Chen, Yuan
Westenbroek, Ruth E.
Brown, Angus
Malhotra, Jyoti Dhar
Jones, Dorothy
Avery, Christy L.
Gillespie, Patrick J., III
Kazen-Gillespie, Kristin A.
Kazarinova-Noyes, Katie
Shrager, Peter G.
Saunders, Thomas L.
Macdonald, Robert L.
Ransom, Bruce R.
Scheuer, Todd
Catterall, William A.
Isom, Lori L.

Year Published

2002

Volume Number

99

Issue Number

26

Pages

17072-7

PMCID

PMC139271

Reference ID

9594