Nax is a protein that in humans is encoded by the SCN7A (Sodium channel protein type 7) gene.[5][6] It is a sodium channel alpha subunit expressed in the heart, the uterus and in glial cells of mice. It has low similarity to all nine other sodium channel alpha subunits (Nav1.1–1.9).[5]
Scientists have so far been unable to create a voltage-gated channel out of SCN7A. There are two theories to its purpose: sodium sensor (confirmed in rats, not reproducible in human cells), and ion channel (proposed for humans).[7]
Mouse Scn7a can be activated by changes in the extracellular concentration of sodium [~150 mM].[8] In this role it seems to be completely insensitve to tetrodotoxin, unlike its nine conventional VGNCs cousins.[9]
Compared to normal mice, Scn7a knockout mice:
Despite all the evidence pointing to Scn7a acting as a sodium sensor in rodents, there is no data for humans, not even in cell cultures. Conditions that confirm the sodium-sensing abilities of mouse Scn7a do not reliably work on human SCN7A.[7]
The cyro-EM structure shows that human SCN7A is normally stuck in a nonconductive state, with several membrane lipid molecules blocking the pore. When three polar "QTT" mutations were added to drive the lipids away from SCN7A, one obtains a leakage channel that is always active. SCN7A-QTT does not discriminate among monovalent cations, is inhibited by extracellular calcium, and is sensitive to tetrodotoxin and other classical sodium channel blockers. This result suggests that SCN7A could actually function as an ion channel, assuming there is a way to displace the lipid molecules in vivo – this type of "hydrophobic gating" is not unheard of in other channels.[7]
Nax is only found in eutherian mammals. It arose by a duplication of the gene SCN9A and quickly deviated from the canonical Nav1 functions by losing key conserved residues in domains III, IV, and the loop in between. As eutherians diverged, Nax showed exceptionally high evolutionary rates across all lineages.[14]
Nax must not be confused with "Nav2" of invertebrates. This other "Nav2" is a true voltage-gated channel in these animals and carry the ancestral "D/E/E/A" ion recognition sequence.[15]
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
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