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Persistent sodium current

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The persistent sodium current (INaP) (also called the "late sodium current" or "non/slow-inactivating sodium current") is a form of sub-threshold, biological electric current contributed by non-inactivating voltage-gated sodium channels (NaVs) found in several central neurons.[1] INaP has been implicated in neuronal excitability, epilepsy, and neuropathic pain.[2][3][4]

The "persistent sodium current" (here shown as INaP) is defined in this instance as the remaining sodium current after fast inactivation that produces the sharp termination of the transient current (INaT). In this particular recording, the red trace shows a Purkinje neuron that was stepped from -90mV to 0mV for 5ms to inactivate all transient current, then repolarized at -45mV for 30ms. The persistent sodium current is best measured at the end of the step.

Biophysics

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Persistent sodium current generation is hypothesized to occur by the incomplete inactivation of the voltage-gated sodium channel current (INa), where the channel becomes constitutively active and conducts sodium, creating a "persistently active" inward sodium current. Upon depolarization, the four identical motifs of the sodium channel (which contain six transmembrane segments that include a pore-forming loop and a voltage sensor) move outward to allow for sodium influx. Sodium channels have the intrinsic ability to close rapidly following depolarization, and this current, named the "transient sodium current" is large and contributes to the bulk of the action potential. However, electrophysiological recordings which isolate INa find small amounts of current following depolarization which slowly inactivates, therefore contributing to the "persistent" or "non-inactivating" sodium current.[5] It is important to note that the persistent sodium current also functions at sub-threshold voltages and is not only measured on depolarization of the membrane, and therefore may modulate neuronal excitability during the interspike interval of action potentials.[6][7]

Health and Disease

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INaP is involved in long QT syndrome, Brugada syndrome, and other inherited arrhythmias.[8] Further, previous research has shown that increases in INaP contributes to hypoxia (medicine),[9] demyelination,[10] paroxysmal extreme pain disorder,[11] and epilepsies.[12][13]

Pharmacological blockers of INaP are used clinically in many of these disorders. Amiodarone, while primarily blocking the human Ether-a-go-go-Related Gene potassium channel, has shown to significantly reduce persistent sodium current by 50% in cortical neurons[14] as well as in cardiac sodium channel NaV1.5 and is used to treat arrhythmia.[15] Cannabidiol has been used as an anti-epileptic for individuals with Dravet syndrome and may block the fast transient and persistent sodium currents, although in high concentration.[16] GS967, also known as Prax330, is used to treat cardiac arrhythmias and surprisingly blocks the persistent sodium current in a study of Dravet syndrome which resulted in reduced seizures.[17]

References

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  1. ^ Crill, W. E. (1996). "Persistent sodium current in mammalian central neurons". Annual Review of Physiology. 58: 349–362. doi:10.1146/annurev.ph.58.030196.002025. PMID 8815799.
  2. ^ Taddese, Abraha; Bean, Bruce P (2002). "Subthreshold Sodium Current from Rapidly Inactivating Sodium Channels Drives Spontaneous Firing of Tuberomammillary Neurons". Neuron. 33 (4): 587–600. doi:10.1016/S0896-6273(02)00574-3. PMID 11856532.
  3. ^ Stafstrom, Carl E. (2007). "Persistent sodium current and its role in epilepsy". Epilepsy Currents. 7 (1): 15–22. doi:10.1111/j.1535-7511.2007.00156.x. PMC 1797888. PMID 17304346.
  4. ^ Waxman, Stephen G.; Hains, Bryan C. (2006). "Fire and phantoms after spinal cord injury: Na+ channels and central pain". Trends in Neurosciences. 29 (4): 207–215. doi:10.1016/j.tins.2006.02.003. PMID 16494954.
  5. ^ Kiss, T (2008). "Persistent Na-channels: origin and function. A review". Acta Biol Hung. 59 (Suppl 1): 1–12. doi:10.1556/ABiol.59.2008.Suppl.1. PMID 18652365.
  6. ^ Taddese, Abraha; Bean, Bruce P. (14 Feb 2002). "Subthreshold sodium current from rapidly inactivating sodium channels drives spontaneous firing of tuberomammillary neurons". Neuron. 33 (4): 587–600. doi:10.1016/s0896-6273(02)00574-3. PMID 11856532.
  7. ^ Stafstrom, Carl E. (2007). "Persistent sodium current and its role in epilepsy". Epilepsy Currents. 7 (1): 15–22. doi:10.1111/j.1535-7511.2007.00156.x. PMC 1797888. PMID 17304346.
  8. ^ Tan, Hanno (May 2006). "Sodium channel variants in heart disease: expanding horizons". J Cardiovasc Electrophysiol. 17 (Suppl 1): S151–S157. doi:10.1111/j.1540-8167.2006.00398.x. PMID 16686672. Retrieved 2 December 2024.
  9. ^ Hammarstrom, A.K.; Gage, P.W. (1 Aug 1998). "Inhibition of oxidative metabolism increases persistent sodium current in rat CA1 hippocampal neurons". J Physiol. 510 (3): 735–741. doi:10.1111/j.1469-7793.1998.735bj.x. PMC 2231084. PMID 9660889.
  10. ^ Hamada, Mustafa S.; Kole, Maarten H.P. (6 May 2015). "Myelin loss and axonal ion channel adaptations associated with gray matter neuronal hyperexcitability". J Neurosci. 35 (18): 7272–7286. doi:10.1523/JNEUROSCI.4747-14.2015. PMC 4420788. PMID 25948275.
  11. ^ Fertleman, Caroline (7 Dec 2006). "SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes". Neuron. 52 (5): 767–774. doi:10.1016/j.neuron.2006.10.006. PMID 17145499.
  12. ^ Vreugdenhil, Martin; Hoogland, Govert; van Veelen, Cornelis W.M.; Wadman, Wytse J. (May 2004). "Persistent sodium current in subicular neurons isolated from patients with temporal lobe epilepsy". Eur J Neurosci. 19 (10): 2769–2778. doi:10.1111/j.1460-9568.2004.03400.x. PMID 15147310.
  13. ^ Lopez-Santiago, Luis F. (2017). "Neuronal hyperexcitability in a mouse model of SCN8A epileptic encephalopathy". Proc Natl Acad Sci U.S.A. 114 (9): 2383–2388. Bibcode:2017PNAS..114.2383L. doi:10.1073/pnas.1616821114. PMC 5338511. PMID 28193882.
  14. ^ Spadoni, Francesca (2 Jul 2002). "Lamotrigine derivatives and riluzole inhibit INa,P in cortical neurons". NeuroReport. 13 (9): 1167–1170. doi:10.1097/00001756-200207020-00019. PMID 12151762.
  15. ^ Ghovanloo, Mohammad-Reza; Abdelsayed, Mena; Ruben, Peter C. (1 Mar 2016). "Effects of Amiodarone and N-desethylamiodarone on Cardiac Voltage-Gated Sodium Channels". Front Pharmacol. 7 (39): 39. doi:10.3389/fphar.2016.00039. PMC 4771766. PMID 26973526.
  16. ^ Müller, Peter; Draguhn, Andreas; Egorov, Alexei V. (Oct 2024). "Persistent sodium currents in neurons: potential mechanisms and pharmacological blockers". Pflugers Arch. 476 (10): 1445–1473. doi:10.1007/s00424-024-02980-7. PMC 11381486. PMID 38967655.
  17. ^ Anderson, Lyndsey L (10 May 2017). "Unexpected Efficacy of a Novel Sodium Channel Modulator in Dravet Syndrome". Sci Rep. 7 (1): 1682. Bibcode:2017NatSR...7.1682A. doi:10.1038/s41598-017-01851-9. PMC 5431801. PMID 28490751.
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