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The Journal of Neuroscience, August 20, 2003, 23(20):7577-7585
 Previous Article | Next Article 
Sodium Channel  4, a New Disulfide-Linked Auxiliary Subunit with Similarity to 2
Frank H. Yu,1
Ruth E. Westenbroek,1
Inmaculada Silos-Santiago,2
Kimberly A. McCormick,1
Deborah Lawson,2
Pei Ge,2
Holly Ferriera,2
Jeremiah Lilly,2
Peter S. DiStefano,2
William A. Catterall,1
Todd Scheuer,1 and
Rory Curtis2
1Department of Pharmacology, University of
Washington, Seattle, Washington 98195-7280, and
2Millennium Pharmaceuticals Inc., Cambridge,
Massachusetts 02139
The principal  subunit of voltage-gated sodium channels is
associated with auxiliary  subunits that modify channel function and
mediate protein-protein interactions. We have identified a new subunit
termed 4. Like the 1-3 subunits, 4 contains a cleaved
signal sequence, an extracellular Ig-like fold, a transmembrane segment, and a
short intracellular C-terminal tail. Using TaqMan reverse transcription-PCR
analysis, in situ hybridization, and immunocytochemistry, we show
that 4 is widely distributed in neurons in the brain, spinal cord, and
some sensory neurons.4 is most similar to the2 subunit (35%
identity), and, like the2 subunit, the Ig-like fold of 4 contains
an unpaired cysteine that may interact with the subunit. Under
nonreducing conditions, 4 has a molecular mass exceeding 250 kDa because
of its covalent linkage to Nav1.2a, whereas on reduction, it
migrates with a molecular mass of 38 kDa, similar to the mature glycosylated
forms of the other subunits. Coexpression of4 with brain
Nav1.2a and skeletal muscle Nav1.4 subunits in
tsA-201 cells resulted in a negative shift in the voltage dependence of
channel activation, which overrode the opposite effects of1 and3
subunits when they were present. This novel, disulfide-linked subunit
is likely to affect both protein-protein interactions and physiological
function of multiple sodium channel subunits.
Key words: sodium channel; auxiliary subunit; 4; cDNA cloning; tissue distribution; disulfide link; voltage dependence of activation
Received Mar. 28, 2003;
revised Jun. 11, 2003;
accepted Jun. 11, 2003.
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