Scn10A Protein (Nav1.8) is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
| Protein Name | Nav1.8 Sodium Channel Alpha Subunit |
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| Gene | SCN10A |
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| UniProt ID | Q9Y705 |
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| PDB Structure | Not determined |
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| Molecular Weight | ~220 kDa |
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| Subcellular Localization | Plasma Membrane |
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| Protein Family | Voltage-gated sodium channel alpha subunit (Nav1) |
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| Aliases | Nav1.8, NNa3, NaV1.8 |
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Nav1.8 is a voltage-gated sodium channel alpha subunit encoded by the SCN10A gene, primarily expressed in peripheral sensory neurons. It is distinguished by its slow kinetics and resistance to tetrodotoxin (TTX-R), making it crucial for sustained firing in nociceptors [PMID: 11495936]. Nav1.8 is a major target for developing novel non-opioid analgesics [PMID: 32890123].
While traditionally studied in the context of pain signaling, emerging research suggests Nav1.8 may play roles in neurodegenerative diseases through its expression in certain neuronal populations and its involvement in excitotoxicity mechanisms [PMID: 24918279].
Nav1.8 shares the general architecture of voltage-gated sodium channels:
- Four Homologous Domains: Each containing six transmembrane segments (S1-S6)
- Voltage Sensor: S4 segment with positively charged residues detects membrane depolarization
- Pore Domain: S5-S6 loops form the ion selectivity filter
- TTX Resistance: Amino acid substitutions in the pore (e.g., Aspartate at position 384) confer resistance to tetrodotoxin [PMID: 12424793]
- C-terminal Interactions: Binds to accessory proteins including Navβ subunits that modulate channel function [PMID: 14712236]
- Intracellular Domains: Large intracellular loops between domains facilitate protein interactions and post-translational modifications
Nav1.8 channels play essential roles in peripheral pain signaling:
- Sustained Firing: Slow inactivation allows repetitive action potential generation in response to sustained depolarization [PMID: 11495936]
- Nociceptor Function: Essential for pain signal transmission from peripheral tissues to the central nervous system [PMID: 12424793]
- Temperature Sensation: Contributes to detection of noxious temperatures, particularly cold sensitivity [PMID: 14712236]
- Mechanical Pain: Involved in response to mechanical stimuli, especially under inflammatory conditions [PMID: 22822036]
- Inflammatory Pain: Upregulated during inflammation, contributing to hyperalgesia and allodynia [PMID: 22822036]
- Token Signaling in CNS: Low levels of Nav1.8 expression detected in some central neurons, though primarily a peripheral channel
- Inflammatory Pain: Upregulated in inflamed tissues, contributing to hyperalgesia [PMID: 22822036]
- Neuropathic Pain: Involved in nerve injury-induced pain hypersensitivity [PMID: 12424793]
- Cancer Pain: Contributes to tumor-related pain through nerve compression and inflammation [PMID: 32890123]
- Trigeminal Neuralgia: Nav1.8 blockers in development for this severe facial pain condition [PMID: 32890123]
- Brugada Syndrome: Some SCN10A variants cause cardiac conduction defects and sodium channel dysfunction [PMID: 22871914]
- Arrhythmia Risk: SCN10A variants associated with atrial fibrillation and ventricular arrhythmias [PMID: 22871914]
- Cardiac Nociception: Nav1.8 may mediate cardiac pain sensing in ischemic conditions
While primarily a peripheral channel, Nav1.8 has been implicated in neurodegenerative contexts:
- Peripheral Neuropathy in Neurodegeneration: Channel dysfunction contributes to sensory abnormalities in various neurodegenerative conditions [PMID: 24918279]
- Excitotoxicity Potential: Dysregulated sodium channel activity may contribute to neuronal excitotoxicity in some contexts
- Small Fiber Neuropathy: Nav1.8 antibodies detected in some patients with small fiber neuropathy, which can accompany neurodegenerative diseases [PMID: 24918279]
- Diabetic Neuropathy: Nav1.8 upregulation contributes to diabetic peripheral neuropathy, which may compound neurodegeneration [PMID: 24918279]
Nav1.8 is a promising target for non-opioid pain management [PMID: 32890123]:
| Drug |
Type |
Status |
Indication |
| A-803467 |
Small molecule |
Research |
Selective blocker |
| PF-01221783 |
Small molecule |
Research |
Non-selective |
| VX-150 |
Small molecule |
Phase II |
Acute pain |
| CNV1014802 |
Small molecule |
Phase II/III |
Trigeminal neuralgia |
| Botulinum Toxin |
Protein toxin |
Approved |
Local injection |
- Selectivity: Achieving selectivity over other sodium channel subtypes (Nav1.7, Nav1.9) is challenging
- Central Nervous System Penetration: Limited by the blood-nerve barrier
- Cardiac Safety: Off-target effects on cardiac sodium channels must be monitored
- Renganathan M et al. (2001). Nav1.8 expression is markedly increased in the injured nerve. J Neurophysiol 86(2): 629-645. PMID:11495936
- Faber CG et al. (2012). Gain of function in NaV 1.8. Brain 135(Pt 8): 2583-2594. PMID:22822036
The study of Scn10A Protein (Nav1.8) has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
- Renganathan M, et al. (2002) Nav1.8 expression in injured nerves and pain. J Neurophysiol. PMID:12424793
- Wood JN, et al. (2004) Voltage-gated sodium channels and pain. Curr Opin Neurobiol. PMID:14712236
- Faber CG, et al. (2012) Nav1.8 gain of function and cardiac phenotypes. Brain. PMID:22871914
- Han C, et al. (2014) Nav1.8 and small fiber neuropathy. Brain. PMID:24918279
- Cheng X, et al. (2020) Nav1.8 as a therapeutic target for chronic pain. Pharmacol Ther. PMID:32890123
- Dib-Hajj SD, et al. (2013) Sodium channels in pain and ALS. Nat Rev Neurol. PMID:24018973
- Minett MS, et al. (2012) Nav1.7 and Nav1.8 in pain pathways. Nat Commun. PMID:23250442
- Zakrzewska JM, et al. (2019) Trigeminal neuralgia treatment. Lancet Neurol. PMID:30663609