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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). All four auxiliary 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).

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.

References associated with 8.A.17 family:

Chen, K.H., X.H. Xu, H.Y. Sun, X.L. Du, H. Liu, L. Yang, G.S. Xiao, Y. Wang, M.W. Jin, and G.R. Li. (2016). Distinctive property and pharmacology of voltage-gated sodium current in rat atrial vs ventricular myocytes. Heart Rhythm 13: 762-770. 26598320
Gurnett, C.A. and K.P. Campbell. (1996). Transmembrane auxiliary subunits of voltage-dependent ion channels. J. Biol. Chem. 271: 27975-27978. 8910401
Hull, J.M. and L.L. Isom. (2017). Voltage-gated sodium channel β subunits: The power outside the pore in brain development and disease. Neuropharmacology. [Epub: Ahead of Print] 28927993
Isom, L.L., D.S. Ragsdale, K.S. De Jongh, R.E. Westenbroek, B.F. Reber, T. Scheuer, and W.A. Catterall. (1995). Structure and function of the beta 2 subunit of brain sodium channels, a transmembrane glycoprotein with a CAM motif. Cell 83: 433-442. 8521473
Johnson, D. and E.S. Bennett. (2006). Isoform-specific effects of the β2 subunit on voltage-gated sodium channel gating. J. Biol. Chem. 281: 25875-25881. 16847056
Kanellopoulos, A.H., J. Koenig, H. Huang, M. Pyrski, Q. Millet, S. Lolignier, T. Morohashi, S.J. Gossage, M. Jay, J.E. Linley, G. Baskozos, B.M. Kessler, J.J. Cox, A.C. Dolphin, F. Zufall, J.N. Wood, and J. Zhao. (2018). Mapping protein interactions of sodium channel Na1.7 using epitope-tagged gene-targeted mice. EMBO. J. 37: 427-445. 29335280
Kubota, T., A.M. Correa, and F. Bezanilla. (2017). Mechanism of functional interaction between potassium channel Kv1.3 and sodium channel NavBeta1 subunit. Sci Rep 7: 45310. 28349975
Molinarolo, S., D. Granata, V. Carnevale, and C.A. Ahern. (2018). Mining Protein Evolution for Insights into Mechanisms of Voltage-Dependent Sodium Channel Auxiliary Subunits. Handb Exp Pharmacol. [Epub: Ahead of Print] 29464397
Morgan, K., E.B. Stevens, B. Shah, P.J. Cox, A.K. Dixon, K. Lee, R.D. Pinnock, J. Hughes, P.J. Richardson, K. Mizuguchi, and A.P. Jackson. (2000). beta 3: an additional auxiliary subunit of the voltage-sensitive sodium channel that modulates channel gating with distinct kinetics. Proc. Natl. Acad. Sci. USA 97: 2308-2313. 10688874
Shimizu, H., A. Tosaki, N. Ohsawa, Y. Ishizuka-Katsura, S. Shoji, H. Miyazaki, F. Oyama, T. Terada, M. Shirouzu, S.I. Sekine, N. Nukina, and S. Yokoyama. (2017). Parallel homodimer structures of the extracellular domains of the voltage-gated sodium channel β4 subunit explain its role in cell-cell adhesion. J. Biol. Chem. [Epub: Ahead of Print] 28655765
Yu, F.H., R.E. Westenbroek, I. Silos-Santiago, K.A. McCormick, D. Lawson, P. Ge, H. Ferriera, J. Lilly, P.S. DiStefano, W.A. Catterall, T. Scheuer, and R. Curtis. (2003). Sodium channel beta4, a new disulfide-linked auxiliary subunit with similarity to beta2. J. Neurosci. 23: 7577-7585. 12930796
Zhu, W., T.L. Voelker, Z. Varga, A.R. Schubert, J.M. Nerbonne, and J.R. Silva. (2017). Mechanisms of noncovalent β subunit regulation of NaV channel gating. J Gen Physiol. [Epub: Ahead of Print] 28720590