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