NAV1.8

Official Full Name

sodium voltage-gated channel alpha subunit 10

Organism

Homo sapiens

GeneID

6336

Background

The protein encoded by this gene is a tetrodotoxin-resistant voltage-gated sodium channel alpha subunit. The properties of the channel formed by the encoded transmembrane protein can be altered by interaction with different beta subunits. This protein may be involved in the onset of pain associated with peripheral neuropathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

Synonyms

SCN10A; PN3; SNS; FEPS2; Nav1.8;

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Detailed Information

The Nav1.8-encoding gene is SCN10A, which is located in the human chromosome 3p21-22 region and encodes the alpha subunit. The study found that human and rat Nav1.8 gene homology is as high as 93%. The Nav1.8 molecule consists of the alpha and beta subunits, which are the main functional units. Each alpha subunit is surrounded by four homologous domains, forming a central pore of Nav1.8. Each domain contains six alpha helical transmembrane structures (S1 to S6), with the conserved S4 being the voltage receptor for the sodium ion channel. There are four subtypes of β subunits, β1 to β4, which are mainly β1 and β3 in humans, which play an auxiliary role in the localization and stability of α in the cell membrane, and also participate in the inactivation and voltage sensitivity of α subunit. The current of Nav1.8 is mainly formed by α, and the β subunit has little effect on its current.

There are nine human sodium channels, Nav1.1 to Nav1.9, and Nav1.5, Nav1.8 and Nav1.9 are tetrodotoxin (TTX) insensitive sodium channels. Among them, Nav1.8 is an important ion channel involved in chronic pain, atrial fibrillation, and Budd-Chiari syndrome, and is a highly selective target for pain treatment. An in-depth study of Nav1.8 helps to clarify the pathogenesis of pain and other related diseases, develop analgesic drugs, and provide a basis for the diagnosis, treatment, and prevention of diseases.

Regulation of Nav1.8 Expression

Nav1.8 is mainly synthesized and secreted intracellularly, and its expression on the cell membrane is controlled by endoplasmic reticulum secretion. The first intracellular loop of Nav1.8, RRR, is responsible for retaining Nav1.8 on the endoplasmic reticulum and limiting its expression in the cell membrane. The -C terminus of the β3 subunit reacts with the inner loop of Nav1.8 cells, concealing the retention restriction signal of the endoplasmic reticulum, thereby promoting the expression of Nav1.8 cell membrane. Immunochemical methods showed that each of the first, second, and third transmembrane segments of Nav1.8 reduced the expression of Nav1.8. Acidic amino acids are a major factor in transmembrane fragments that affect the expression of Nav1.8 by interacting with calnexin. Overexpression of cadherin leads to an increase in Nav1.8 degradation through an endoplasmic reticulum-associated degenerative pathway, thereby reducing vascular expression in Nav1.8.

Figure 1. Schematic summary of potential pathways of Nav1.8 for regulating cardiac function. (Chen, X., et al. 2016)

Aquaporins 1 (AQP1) are important molecules involved in the perception of heat inflammatory pain and cold pain. Immunoprecipitation showed that nav1.8 and AQP1 interacted with each other, accelerating the inactivation of Nav1.8 in AQP1 -/- mice at the molecular level. Pyruvic aldehyde is one of the important causes of diabetic pain, which induces depolarized Nav1.8 post-translational modification, thereby activating Nav1.8. Studies have shown that pyruvate-induced streptozotocin diabetes model hyperalgesia is achieved by activating transient receptor potential A1 (TRPA1) and Nav1.8. Therefore, Nav1.8 also plays an important role in pathological pain in diabetes.

The Role of Nav1.8 in Pain

Complete Freund's adjuvant (CFA) injection resulted in phosphorylation of PKB/Akt (protein kinase B, PKB) and an increase in Nav1.8. The use of Akt blockers eliminates the hyperalgesia caused by CFA and the increase in Nav1.8. In the chronic inflammation model, LV1.8 mRNA in the trigeminal nerve increased 2.5-fold after 1 to 2 weeks after CFA injection. Intrathecal injection of Nav1.8 antisense nucleotides blocked spontaneous pain and hyperalgesia caused by SNL model and CFA. After ten days of sciatic nerve compression, injection of Nav1.8 antisense nucleotides reduced mechanical allodynia. Sustained inflammatory sensitization by CFA increased the intensity of Na⁺ and Nav1.8 peak currents in Nav1.8, Aβ afferent nerve fibers. In the chronic neuropathic pain models such as SNI, SNL, and CCI, the expression of Nav1.8 was up-regulated in the corresponding dorsal root ganglia.

References:

Huang, Q. , Chen, Y. , Gong, N. , & Wang, Y. X. . (2016). Methylglyoxal mediates streptozotocin-induced diabetic neuropathic pain via activation of the peripheral trpa1 and nav1.8 channels. Metabolism, 65(4), 463-474.
Savio-Galimberti, E. , Weeke, P. , Muhammad, R. , Blair, M. , Ansari, S. , & Short, L. , et al. (2014). Scn10a/nav1.8 modulation of peak and late sodium currents in patients with early onset atrial fibrillation. Cardiovascular Research, 104(2), 355-363.
Chen, X., Yu, L., Shi, S., Jiang, H., Huang, C., & Desai, M., et al. (2016). Neuronal nav1.8 channels as a novel therapeutic target of acute atrial fibrillation prevention. Journal of the American Heart Association Cardiovascular & Cerebrovascular Disease, 5(11), e004050.

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