Reaction: SCNAs:SNCBs transport Na+ from extracellular region to cytosol
- in pathway: Phase 0 - rapid depolarisation
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).
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).
Reaction - small molecule participants:
Na+ [cytosol]
Na+ [extracellular region]
Reactome.org reaction link: R-HSA-5576895
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Reaction input - small molecules:
sodium(1+)
Reaction output - small molecules:
sodium(1+)
Reactome.org link: R-HSA-5576895