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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.


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.

SUBMITTER: Chen C 

PROVIDER: S-EPMC139271 | biostudies-literature | 2002 Dec

REPOSITORIES: biostudies-literature

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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.

Chen Chunling C   Bharucha Vandana V   Chen Yuan Y   Westenbroek Ruth E RE   Brown Angus A   Malhotra Jyoti Dhar JD   Jones Dorothy D   Avery Christy C   Gillespie Patrick J PJ   Kazen-Gillespie Kristin A KA   Kazarinova-Noyes Katie K   Shrager Peter P   Saunders Thomas L TL   Macdonald Robert L RL   Ransom Bruce R BR   Scheuer Todd T   Catterall William A WA   Isom Lori L LL  

Proceedings of the National Academy of Sciences of the United States of America 20021212 26


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 inactiva  ...[more]

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