Reduced sodium channel density, altered voltage dependence of inactivation, and increased susceptibility to seizures in mice lacking sodium channel beta 2-subunits.
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.
Chen
Chunling
C
Departments of Pharmacology and Neurology, and Transgenic Animal Model Core Laboratory, University of Michigan, Ann Arbor, MI 48109, USA.
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
D000200:Action Potentials; D000818:Animals; D004198:Disease Susceptibility; D051379:Mice; D018345:Mice, Knockout; D009412:Nerve Fibers / Q000502:physiology; D009431:Neural Conduction; D010862:Pilocarpine / Q000494:pharmacology; D021122:Protein Subunits; D012640:Seizures / Q000209:etiology*; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000032:analysis / Q000502:physiology*
D021122:Protein Subunits; D015222:Sodium Channels; D010862:Pilocarpine; D012964:Sodium