SCNAs:SNCBs transport Na+ from extracellular region to cytosol

Stable Identifier
R-HSA-5576895
Type
Reaction [transition]
Species
Homo sapiens
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Sodium channel proteins, subunit alpha (SCNAs) mediate the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na+ ions may pass in accordance with their electrochemical gradient. SCNA channels consist of an ion-conducting, pore-forming alpha-subunit regulated by one or more associated auxiliary subunits SCN1B, 2B, 3B and 4B. SCN1B and 3B are non-covalently associated with SCNA, while SCN2B is covalently linked by disulfide bonds.

SCNAs interact with cytosolic proteins that regulate channel trafficking and/or modulate the biophysical properties of the channels. Fibroblast growth factors (FGFs) are potent regulators of voltage-gated Na+ channels in adult ventricular myocytes and suggest that loss-of-function mutations in FGFs may underlie a similar set of cardiac arrhythmias and cardiomyopathies that result from SCN5A (aka Nav1.5) loss-of-function mutations. Ran guanine nucleotide release factor (RANGRF aka MOG1) is a critical regulator of sodium channel function in the heart and is thought to regulate the cell surface localization of SCN5A (Marfatia et al. 2001, Wu et al. 2008). Calcium/calmodulin-dependent protein kinase type II subunit delta (CAMK2D), as part of a heteromeric complex with CAMK2A, CAMK2B and CAMK2G can be activated by calmodulin/Ca2+ (CALM:4xCa2+) to then phosphorylate SNC5A at multiple sites, inactivating it (Ashpole et al. 2012).

Literature References
PubMed ID Title Journal Year
14500339 A ubiquitous splice variant and a common polymorphism affect heterologous expression of recombinant human SCN5A heart sodium channels

Makielski, JC, Ye, B, Valdivia, CR, Pagel, MD, Pu, J, Tester, DJ, Ackerman, MJ

Circ. Res. 2003
21566136 Identification of novel interaction sites that determine specificity between fibroblast growth factor homologous factors and voltage-gated sodium channels

Wang, C, Wang, C, Hoch, EG, Pitt, GS

J. Biol. Chem. 2011
1309946 Primary structure and functional expression of the human cardiac tetrodotoxin-insensitive voltage-dependent sodium channel

Gellens, ME, George, AL, Chen, LQ, Chahine, M, Horn, R, Barchi, RL, Kallen, RG

Proc. Natl. Acad. Sci. U.S.A. 1992
11290418 Identification and characterization of the human MOG1 gene

Marfatia, KA, Harreman, MT, Fanara, P, Vertino, PM, Corbett, AH

Gene 2001
18184654 Identification of a new co-factor, MOG1, required for the full function of cardiac sodium channel Nav 1.5

Wu, L, Yong, SL, Fan, C, Ni, Y, Yoo, S, Zhang, T, Zhang, X, Obejero-Paz, CA, Rho, HJ, Ke, T, Szafranski, P, Jones, SW, Chen, Q, Wang, QK

J. Biol. Chem. 2008
21817159 Fibroblast growth factor homologous factor 13 regulates Na+ channels and conduction velocity in murine hearts

Wang, C, Hennessey, JA, Kirkton, RD, Wang, C, Graham, V, Puranam, RS, Rosenberg, PB, Bursac, N, Pitt, GS

Circ. Res. 2011
23804213 Fibroblast growth factor homologous factors modulate cardiac calcium channels

Hennessey, JA, Wei, EQ, Pitt, GS

Circ. Res. 2013
22514276 Ca2+/calmodulin-dependent protein kinase II (CaMKII) regulates cardiac sodium channel NaV1.5 gating by multiple phosphorylation sites

Ashpole, NM, Herren, AW, Ginsburg, KS, Brogan, JD, Johnson, DE, Cummins, TR, Bers, DM, Hudmon, A

J. Biol. Chem. 2012
19406745 Crystal structure of a fibroblast growth factor homologous factor (FHF) defines a conserved surface on FHFs for binding and modulation of voltage-gated sodium channels

Goetz, R, Dover, K, Laezza, F, Shtraizent, N, Huang, X, Tchetchik, D, Eliseenkova, AV, Xu, CF, Neubert, TA, Ornitz, DM, Goldfarb, M, Mohammadi, M

J. Biol. Chem. 2009
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Catalyst Activity
Title
voltage-gated sodium channel activity of SCNAs:SCNBs [plasma membrane]
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