Mice lacking sodium channel beta1 subunits display defects in neuronal excitability, sodium channel expression, and nodal architecture.
Sodium channel beta1 subunits modulate alpha subunit gating and cell surface expression and participate in cell adhesive interactions in vitro. beta1-/- mice appear ataxic and display spontaneous generalized seizures. In the optic nerve, the fastest components of the compound action potential are slowed and the number of mature nodes of Ranvier is reduced, but Na(v)1.6, contactin, caspr 1, and K(v)1 channels are all localized normally at nodes. At the ultrastructural level, the paranodal septate-like junctions immediately adjacent to the node are missing in a subset of axons, suggesting that beta1 may participate in axo-glial communication at the periphery of the nodal gap. Sodium currents in dissociated hippocampal neurons are normal, but Na(v)1.1 expression is reduced and Na(v)1.3 expression is increased in a subset of pyramidal neurons in the CA2/CA3 region, suggesting a basis for the epileptic phenotype. Our results show that beta1 subunits play important roles in the regulation of sodium channel density and localization, are involved in axo-glial communication at nodes of Ranvier, and are required for normal action potential conduction and control of excitability in vivo.
Chen
Chunling
C
Department of Pharmacology,The University of Michigan, Ann Arbor, Michigan 48109-0632, USA.
Westenbroek
Ruth E
RE
Xu
Xiaorong
X
Edwards
Chris A
CA
Sorenson
Dorothy R
DR
Chen
Yuan
Y
McEwen
Dyke P
DP
O'Malley
Heather A
HA
Bharucha
Vandana
V
Meadows
Laurence S
LS
Knudsen
Gabriel A
GA
Vilaythong
Alex
A
Noebels
Jeffrey L
JL
Saunders
Thomas L
TL
Scheuer
Todd
T
Shrager
Peter
P
Catterall
William A
WA
Isom
Lori L
LL
D000200:Action Potentials / Q000502:physiology; D000818:Animals; D001259:Ataxia / Q000150:complications / Q000235:genetics; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism; D002478:Cells, Cultured; D058966:Contactins; D004392:Dwarfism / Q000150:complications / Q000235:genetics; D004827:Epilepsy / Q000150:complications / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D062550:NAV1.1 Voltage-Gated Sodium Channel; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000648:ultrastructure; D018408:Patch-Clamp Techniques; D010641:Phenotype; D015221:Potassium Channels / Q000378:metabolism; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D017966:Pyramidal Cells / Q000378:metabolism; D011901:Ranvier's Nodes / Q000648:ultrastructure*; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism; D015996:Survival Rate
D015816:Cell Adhesion Molecules, Neuronal; C491322:Cntnap1 protein, mouse; D058966:Contactins; D062550:NAV1.1 Voltage-Gated Sodium Channel; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D015221:Potassium Channels; D021122:Protein Subunits; C568249:Scn1a protein, mouse; C491046:Scn8a protein, mouse; D015222:Sodium Channels; D012964:Sodium