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 (Nav1.5) by causing a hyperpolarizing shift in voltage-dependent gating (Johnson and Bennett, 2006). By contrast, sialic acid-free β2 caused a depolarizing shift in Nav1.2. 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.



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TC#NameOrganismal TypeExample

Sodium channel ß1 (β-1, beta-1) subunit.  This subunit can interact with and regulate the activity of the K+ channel, Kv10.1 of the KCNH family (TC# 1.A.1.2.17), as well as of Na+ channels (Kubota et al. 2017). Both beta1 and beta3 subunits regulate channel gating, expression, and pharmacology. Beta1 regulates NaV1.5 by modulating the 4th voltage-sensing domain, DIV-VSD, whereas beta3 alters channel kinetics mainly through the DIII-VSD interaction (Zhu et al. 2017). An SCN1B variant affects both cardiac-type (NaV1.5) and brain-type (NaV1.1) sodium currents and contributes to complex concomitant brain and cardiac disorders (Martinez-Moreno et al. 2020). Mice null for Scn1b, which encodes NaV beta1 and beta1b subunits, have defects in neuronal development and excitability, spontaneous generalized seizures, cardiac arrhythmias, and early mortality.

Vertebrate animals

Navß1 (Navbeta1) of Homo sapiens (Q07699)


Sodium channel beta3 (ß3)-subunit (Morgan et al. 2000). It interacts with Na+ channel, Nav1.7 (Kanellopoulos et al. 2018) as well as Nav1.5. Gating control of the cardiac sodium channel Nav1.5 by its beta3-subunit involves distinct roles for a transmembrane glutamic acid and the extracellular domain (Salvage et al. 2019).


Vertebrate animals

ß3 from Homo sapiens (Q9NY72)


TC#NameOrganismal TypeExample

Sodium channel β2 subunit of 1040 aas and 1 or 2 TMSs, at the C-terminus and possibly at the N-terminus.  Distinctive biophysical properties of INa in atrial and ventricular myocytes can be attributed to inhomogeneous expression of NaVβ2 and NaVβ4 subunits, and atrial INa is more sensitive to inhibition by dronedarone (Chen et al. 2016).

Vertebrate animals

β2 from Homo sapiens (O60939)


Sodium channel β4 subunit. 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 alpha-beta4 complex formation.

Vertebrate animals

β4 from Homo sapiens (Q8IWT1)


TC#NameOrganismal TypeExample
Immune-type receptor 4 of 280 aas and 2 TMSs.


Immune-type receptor 4 of Ictalurus punctatus

Uncharacterized protein of 265 aas and 2 or 3 potential TMSs, one near the N-terminus, and one near the C-terminus.  The protein shows two internal repeats, involving residues 54 - 110 and 186 - 249.

UP of Danionella translucida


Uncharacterized protein of 259 aas and 2 TMSs.

UP of Pangasianodon hypophthalmus (striped catfish)


Uncharacterized protein of 330 aas and 1 TMS near the C-terminus.

UP of Xiphophorus couchianus (Monterrey platyfish)


T cell receptor alpha chain of 258 aas and 2 TMSs, N- and C-terminal.

T cell receptor α of Stegastes partitus (bicolor damselfish)


TC#NameOrganismal TypeExample

Programmed cell death protein 1, PDCD1 or PD1, of 288 aas and one TMS at positions ~170 - 190. It is an inhibitory receptor on antigen activated T-cells that plays a critical role in induction and maintenance of immune tolerance to self (Fife and Pauken 2011) and delivers inhibitory signals upon binding to ligands CD274/PDCD1L1 and CD273/PDCD1LG2 (Fife and Pauken 2011). Following T-cell receptor (TCR) engagement, PDCD1 associates with CD3-TCR in the immunological synapse and directly inhibits T-cell activation. PD-1 is expressed on innate lymphoid-2 (ILC2) cells and plays a role in ani-tumor activities (Jacquelot et al. 2021).


PD1 of Homo sapiens