NaV1.8 channels
| Channel name | NaV1.8 |
| Description | Voltage-gated sodium channel α subunit |
| Other names | SNS, PN3 |
| Molecular information | Human: 1957aa, Q9Y5Y9, NM_006514, chr. 3P21-3P24, SCN10A |
| Rat: Q63554, Q62968, NM_017247, U53833 | |
| Mouse: P70276, NM_009134, chr. 9 | |
| Associated subunits | Not established |
| Functional assays | Voltage-clamp, voltage-sensitive dyes |
| Current | ITTX-Rslow |
| Conductance | Not established |
| Ion selectivity | Na+ |
| Activation | Threshold = –40 to –30 mV (rat DRG)1,2 |
| Va = –16 to –21 mV (rat DRG)1,2 | |
| τa = 0.54 ms at –20 mV, 0.36 ms at –10 mV | |
| Inactivation | Vh = ∼–30 mV (rat DRG), τh = 13.5 ms at –20mV, 5.6 ms at –10 mV |
| Activators | Not established |
| Gating modifiers | Not established |
| Blockers | Tetrodotoxin (TTX-resistant, EC50 = 60 mM), lidocaine (and probably other local anesthetics) at high concentrations3 |
| Radioligands | None |
| Channel distribution | Small and medium-sized DRG neurones and their axons4 |
| Physiological functions | Contributes substantially to the inward current underlying the action potential in DRG neurones5; adds a slowly inactivating sodium current component |
| Mutations and pathophysiology | Point mutation of Ser356 to an aromatic residue removes TTX resistance6; NaV1.8-null mice exhibit reduced pain responses to noxious mechanical stimuli, delayed development of inflammatory hyperalgesia, and small deficits in noxious thermoreception,7 suggesting a role of Nav1.8 in nociception and in chronic pain; Nav1.8 is up-regulated in some models of inflammatory pain8 |
| Pharmacological significance | Potential target for analgesic drugs |
| Comments | Rapid recovery from inactivation is conferred by a three-amino acid insert in IVS3–S49; expression is regulated by NGF and GDNF10; insertion of functional Nav1.8 channels in cell membrane is facilitated by annexin II/p1111 |
aa, amino acids; chr., chromosome; TTX, tetrodotoxin; DRG, dorsal root ganglion; NGF, nerve growth factor; GDNF, glial cell-derived growth factor.
↵1. Cummins TR and Waxman SG (1997) Down-regulation of tetrodotoxin-resistant sodium currents and upregulation of a rapidly repriming tetrodotoxin-sensitive sodium current in small spinal sensory neurons after nerve injury. J Neurosci 17:3503-3514
↵2. Sleeper AA, Cummins TR, Hormuzdiar W, Tyrrell L, Dib-Hajj SD, Waxman SG, and Black JA (2000) Changes in expression of two tetrodotoxin-resistant sodium channels and their currents in dorsal root ganglion neurons following sciatic nerve injury, but not rhizotomy. J Neurosci 20:7279-7289
↵3. Akopian AN, Sivilotti L, and Wood JN (1996) A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. Nature 379:257-262
↵4. Djouri L, Fang X, Okuse K, Wood JN, Berry CM, and Lawson SM (2003) The TTX-resistant sodium channel Nav1.8 (SNS/PN3): expression and correlation with membrane properties in rat nociceptive primary afferent neurons. J Physiol (Lond) 550:739-752
↵5. Renganathan M, Cummins TR, and Waxman SG (2001) Contribution of Nav1.8 sodium channels to action potential electrogenesis in DRG neurons. J Neurophysiol 86:629-640
↵6. Sivilotti L, Okuse K, Akopian AN, Moss S, and Wood JN (1997) A single serine residue confers tetrodotoxin insensitivity on the rat sensory-neuron-specific sodium channel SNS. FEBS Lett 409:49-52
↵7. Akopian AN, Souslova V, England S, Okuse K, Ogata N, Ure J, Smith A, Kerr BJ, McMahon SB, Boyce S, et al. (1999) The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways. Nat Neurosci 2:541-548
↵8. Tanaka M, Cummins TR, Ishikawa K, Dib-Hajj SD, Black JA, and Waxman SG (1998) SNS Na+ channel expression increases in dorsal root ganglion neurons in the carrageenan inflammatory pain model. Neuroreport 9:967-972
↵9. Dib-Hajj SD, Ishikawa I, Cummins TR, and Waxman SG (1997) Insertion of a SNS-specific tetrapeptide in the S3-S4 linker of D4 accelerates recovery from inactivation of skeletal muscle voltage-gated Na channel μ1 in HEK293 cells. FEBS Lett 416:11-14
↵10. Cummins TR, Black JA, Dib-Hajj SD, and Waxman SG (2000) GDNF up-regulates expression of functional SNS and NaN sodium channels and their currents in axotomized DRG neurons. J Neurosci 20:8754-8761
↵11. Okuse K, Malik-Hall M, Baker MD, Poon W-YL, Kong H, Chao M, and Wood JN (2002) Annexin II light chain regulates sensory neuron-specific sodium channel expression. Nature (Lond) 417:653-656