Ka. Mccormick et al., The extracellular domain of the beta 1 subunit is both necessary and sufficient for beta 1-like modulation of sodium channel gating, J BIOL CHEM, 274(46), 1999, pp. 32638-32646
The type IIA voltage-gated sodium Na+ channel from rat brain is composed of
a large, pore-forming alpha subunit and the auxiliary subunits beta 1 and
beta 2. When expressed in Xenopus oocytes, the beta 1 subunit modulates the
gating properties of the type IIA alpha subunit, resulting in acceleration
of both inactivation and recovery from inactivation and in a negative shif
t in the voltage dependence of fast inactivation. The beta 1 subunit is com
posed of an extracellular domain with a single immunoglobulin-libe fold, a
single transmembrane segment, and a small intracellular domain. A series of
chimeras with exchanges of domains between the Na+ channel beta 1 and beta
2 subunits and between pi and the structurally related protein myelin P0 w
ere constructed and analyzed by two-microelectrode voltage clamp in Xenopus
oocytes. Only chimeras containing the pi extracellular domain were capable
of beta 1-like modulation of Na+ channel gating. Neither the transmembrane
segment nor the intracellular domain was required for modulation, although
mutation of Glu(158) within the transmembrane domain altered the voltage d
ependence of steady-state inactivation. A truncated beta 1 subunit was engi
neered in which the pi extracellular domain was fused to a recognition sequ
ence for attachment of a glycosylphosphatidylinositol membrane anchor. The
beta 1(ec)-glycosylphosphatidylinositol protein fully reproduced modulation
of Na+ channel inactivation and recovery from inactivation by wild-type be
ta 1. Our findings demonstrate that extracellular domain of the beta 1 subu
nit is both necessary and sufficient for the modulation of Na+ channel gati
ng.