8.A.17 The Na⁺ Channel Auxiliary Subunit β1-β4 (SCA-β) Family

The SCA-β family of Na⁺ channel auxiliary subunits consists of vertebrate glycoproteins. The principal subunit (α) is the voltage-gated Na⁺ channel (TC #1.A.1.10). The two auxiliary β-subunits probably possess 2 TMSs with the N- and C-termini in the cytoplasm and the extracellular loops between TMSs 1 and 2 bearing glycosylation sites (Gurnett and Campbell 1996). The β1 and β3 subunits modulate the channel-gating kinetics of voltage-sensitive sodium channels. VGSCs are heterotrimeric complexes consisting of a single pore-forming α-subunit joined by two β-subunits; a noncovalently linked beta1 or beta3 and a covalently linked beta2 or beta4 subunit (Hull and Isom 2017). VGSC β-subunits confer unique gating mechanisms, regulate cellular excitability, affect brain development, confer distinct channel pharmacology, and have functions that are independent of the α-subunits. The vast array of functions of these proteins stems from their special station in the channelome: being the only known constituents that are cell adhesion and intra/extracellular signaling molecules in addition to being part of channel complexes (Hull and Isom 2018).

β-subunits possess extracellular immunoglobulin-like domains with similarity to the neural cell adhesion molecule (N-CAM). Coexpression of β2 with the Na⁺ channel α-subunit increases functional expression, so the former may play a role in biogenesis. It also modulates gating and increases capacitance (Isom et al. 1995). Unlike other auxiliary subunits for ion channels, the sodium channel β2- and β4-subunits associate with the α-subunit via a disulfide bond. The structure of β2 can be heavily impacted by the presence of reducing agents. Therefore, it is possible that β2 and β4 form a stable and permanent complex with the pore-forming subunit (Yu et al. 2003). The beta4 cis dimer contributes to the trans homophilic interaction of beta4 in cell-cell adhesion, and may exhibit increased association with the alpha subunit (Shimizu et al. 2017). Thus, the cis dimerization of beta4 probably affects the alpha-beta4 complex formation.

Sialic acid linked to β1 or β2 alters channel gating in Na⁺ channel 1.5 (Na_v1.5) by causing a hyperpolarizing shift in voltage-dependent gating (Johnson and Bennett, 2006). By contrast, sialic acid-free β2 caused a depolarizing shift in Na_v1.2. β2 modulates Na channel gating through multiple mechanisms, and β-subunits modulate multiple isoforms of related voltage-gated potassium channels as well as sodium channels.  The gene family for these single TMS immunoglobulin beta-fold proteins includes cell adhesion proteins and myelin-related proteins - where inherited mutations result in a myriad of electrical signaling disorders (Molinarolo et al. 2018). Structural analyses suggest that the TMSs are key to subunit interactions.