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Abstract
Voltage-gated Na+ channels (VGSCs) in mammals contain a pore-forming α subunit and one or more β subunits. There are five mammalian β subunits in total: β1, β1B, β2, β3, and β4, encoded by four genes: SCN1B–SCN4B. With the exception of the SCN1B splice variant, β1B, the β subunits are type I topology transmembrane proteins. In contrast, β1B lacks a transmembrane domain and is a secreted protein. A growing body of work shows that VGSC β subunits are multifunctional. While they do not form the ion channel pore, β subunits alter gating, voltage-dependence, and kinetics of VGSCα subunits and thus regulate cellular excitability in vivo. In addition to their roles in channel modulation, β subunits are members of the immunoglobulin superfamily of cell adhesion molecules and regulate cell adhesion and migration. β subunits are also substrates for sequential proteolytic cleavage by secretases. An example of the multifunctional nature of β subunits is β1, encoded by SCN1B, that plays a critical role in neuronal migration and pathfinding during brain development, and whose function is dependent on Na+ current and γ-secretase activity. Functional deletion of SCN1B results in Dravet Syndrome, a severe and intractable pediatric epileptic encephalopathy. β subunits are emerging as key players in a wide variety of physiopathologies, including epilepsy, cardiac arrhythmia, multiple sclerosis, Huntington’s disease, neuropsychiatric disorders, neuropathic and inflammatory pain, and cancer. β subunits mediate multiple signaling pathways on different timescales, regulating electrical excitability, adhesion, migration, pathfinding, and transcription. Importantly, some β subunit functions may operate independently of α subunits. Thus, β subunits perform critical roles during development and disease. As such, they may prove useful in disease diagnosis and therapy.
Highlights
Mammalian voltage-gated Na+ channels (VGSCs) exist as macromolecular complexes in vivo, comprising, at minimum, one poreforming α subunit and one or more β subunits in a 1:1 stoichiometry for α:β (Catterall, 1992)
VGSC β subunits have been termed “auxiliary.” increasing evidence suggests that the β subunits are far from auxiliary, and, function as critical signaling molecules in their own right, perhaps even independently of α subunits
Five β subunits have been identified in mammals: β1, its alternative splice variant β1B, β2, β3, and β4 (Isom et al, 1992, 1995; Kazen-Gillespie et al, 2000; Morgan et al, 2000; Qin et al, 2003; Yu et al, 2003)
Summary
Mammalian voltage-gated Na+ channels (VGSCs) exist as macromolecular complexes in vivo, comprising, at minimum, one poreforming α subunit and one or more β subunits in a 1:1 stoichiometry for α:β (Catterall, 1992). With the exception of β1B, the β subunits share a similar type I membrane topology, including an extracellular N-terminal region immunoglobulin (Ig) loop, one transmembrane domain, and a small intracellular C-terminal domain (Figure 2). Mutation studies have revealed that the A/A strand of the β1 Ig fold contains critical charged residues that interact with, and modulate the activity of, the α subunit whereas the intracellular domain is not involved (Mccormick et al, 1998). Β1B shares the same N-terminal Ig domain as β1, but by virtue of retention of intron 3, has a different C-terminal region that lacks a transmembrane domain but contains a stop codon and polyadenylation site (Kazen-Gillespie et al, 2000; Qin et al, 2003). Further species-specific alternative splicing events have been discovered within SCN1B, including splice variants of www.frontiersin.org
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