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Very helpful review paper

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3809569/

The AIS is the membrane domain at the proximal end of the axon in which sodium channels are highly concentrated, electrical signals from the soma and dendrites are summed, and the threshold for action potential initiation is lowest (Royeck et al., 2008). The channel composition of the AIS appears to determine the firing threshold for different types of neurons (Lorincz and Nusser, 2008). Nav1.6 is highly concentrated in the distal half of the AIS in many neurons, including cerebellar granule cells and cerebellar Purkinje cells (Van Wart and Matthews, 2006; Lorincz and Nusser, 2008; Royeck et al., 2008). In the absence of Nav1.6, there is relocation of Nav1.1 and Nav1.2 to occupy the distal AIS (Van Wart and Matthews, 2006; Xiao et al., 2013). Cultured hippocampal CA1 pyramidal cells from Scn8a-null mice exhibit a 5 mV depolarizing (rightward) shift in the voltage dependence of activation, 60% reduction in persistent current, and 75% reduction in resurgent current (Royeck et al., 2008). This combination renders Scn8a null neurons less excitable than their wild type counterparts, as demonstrated by an 8 mV depolarizing shift in the spike threshold (Royeck et al., 2008).

Function edit

Nav1.6 is encoded by the SC8NA gene which contains 27 exons and measures 170 kb. The voltage gated sodium channel is composed of 1980 residues. Like other sodium channels, Nav1.6 is a monomer composed of four homologous domains and 25 transmembrane segments. SC8NA is regulated by exons 5N/5A and 18N/18A. 5N/5A and 18N/18A exons encode S3-S4 transmembrane segments that form an intracellular loop.

Like other sodium channels, Nav1.6 facilitates action potential propagation when the membrane potential is depolarized by an influx of Na+ ions. However, the activation threshold of Nav1.6 is lower compared to other common sodium channels such as Nav1.2. This feature allows Nav1.6 channels to rapidly recover from inactivation and sustain and high rate of activity. [1] The high frequency firing characteristic of Nav1.6 is caused by a persistent and resurgent sodium current. This characteristic is caused by slow activation of the sodium channel following repolarization [2], which allows a steady-state sodium current after the initial action potential propagation. The steady-state sodium current contributes to the depolarization of the following action potential.

Nav1.6 is expressed primarily in the nodes of Ranvier in myelinated axons but is also highly concentrated at the distal end of the axon hillock, cerebellar granule cells and Purkinje neurons.[1] Given the location of Nav1.6, the channel contributes to the firing threshold of a given neuron, as the electrical impulses from various inputs are summated at the axon hillock before propagating down the axon. Other sodium channel isoforms are expressed at the distal end of the axon hillock, including Nav1.1 and Nav1.2. In early stages of myelination, Nav1.2 channels outnumber Nav1.6. However, Nav1.6 gradually replaces the other channels as myelination continues.[3]

Nav1.6 is also present at lower abundance in non-myelinated axons, neuronal soma, and dendrites

Nav1.2 channels are very sensitive to regulation by protein phosphorylation, resulting in a reduction of peak sodium currents (Cantrell et al., 1996, 1997; Carr et al., 2002, 2003; Chen et al., 2005, 2006; Li et al., 1992; Numann et al., 1991). In contrast, we find here that Nav1.6 channels are largely refractory to modulation by PKA or PKC. This striking difference in sodium channel regulation is likely to have important physiological significance.

In hippocampal pyramidal neurons, peak sodium currents are substantially reduced by dopamine acting at D1-like receptors and acetylcholine acting at muscarinic acetylcholine receptors through phosphorylation by PKA and PKC (Cantrell et al., 1996, 1997). This voltage-dependent reduction in peak sodium current reflects enhanced slow inactivation (Chen et al., 2006). In prefrontal cortex neurons, stimulation of 5-HT2A/C receptors activates PKC, reduces Na+ current, increases spike threshold, and reduces spike train duration (Carr 2002, 2003). These effects are also caused by enhancement of slow inactivation by PKC phosphorylation (Carr et al., 2003; Chen et al., 2006). The lack of modulation of NaV1.6 channels by these protein phosphorylation pathways indicates that these channels do not contribute to neurotransmitter modulation of sodium channel function via the PKA and PKC pathways, and therefore do not contribute substantially to modulation of threshold and firing pattern via this mechanism. These results are consistent with the findings of Maurice et al. (2004) that deletion of NaV1.6 channels in knockout mice does not alter the regulation of persistent sodium currents by dopamine activation of the PKA pathway.

Inspection of the amino acid sequences of the phosphorylation sites in NaV1.2 channels and their potential counterparts in Nav1.6 channels indicates a clear molecular basis for the difference in regulation of these two channel types (Table 1). The protein kinase modulation sites in LI–II of the NaV1.2 channel are nearly exactly conserved in NaV1.1 channels, which have comparable modulation by PKA and PKC (Chen et al., unpublished results), but are not well-conserved in the NaV1.6 channel. In particular, the amino acid sequence contexts of the phosphorylation sites at Ser573 and Ser687 in NaV1.2 channels are altered such that phosphorylation of the corresponding sites by PKA and PKC is much less likely in NaV1.6 channels. Evidently, the molecular properties of the NaV1.6 channel prevent its effective modulation by the PKA and PKC pathways.

NaV1.6 channels demonstrate resistance against protein phosphorylation regulation. Sodium channels are modulated by PKA and PKC phosphorylation, which reduce peak sodium currents. Dopamine and acetycholine reduce sodium currents in hippocampal pyramidal neurons through phosphorylation. Similarly, serotonin receptors in the prefrontal cortex are regulated by PKC in order to reduce sodium currents. Phosphorylated regulation in sodium channels helps to slow inactivation.

However, NaV1.6 channels lacks adequate protein kinase sites. Phosphorylation sites Ser573 and Ser687 found in other sodium channels are not well conserved in NaV1.6, leading to the channels ability to consistently and quickly fire following inactivation.

Relationship with Ca2+/CaM in channel activation https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3743062/

Clinical Significance edit

The first known mutation humans was discovered by Krishna Veeramah and Michael Hammer in 2012.[4] The genome of a child demonstrating epileptic encephalopathy was sequenced and revealed a de novo missense mutation, p.Asn1768Asp. The missense mutations in Nav1.6 increased the duration of the persistent sodium current and prevented complete inactivation following hyperpolarization. In addition to epileptic encephalopathy, the patient presented with developmental delay, autistic features, intellectual disability and ataxia.

Mutations causing intellectual disability

Arg1617Gln in domain 4

Predisposition to intellectual disability, normal motor function, lack of abnormalities

History edit

Include the following information

First purified 30 years ago

cDNA clones isolated

Scn8a identified in 1995 by positional cloning of mouse

Isolation of novel sodium channel from rat

Role in relationship to other sodium channels

Can include the following section but will rework

The ion channel was discovered by John Caldwell in the rat,[5] and by Miriam Meisler in the mouse.[6]

Direct evidence for the in vivo role of Nav1.6 has been advanced by recordings from neurons from several different lines of Scn8a null and conditional null mice developed in our laboratory (Burgess et al., 1995; Levin and Meisler, 2004; Levin et al., 2006) (Table ​(Table1).1). Reduced repetitive firing is consistently observed in cerebellar Purkinje cells, granule neurons, trigeminal mesencephalic neurons, and retinal ganglion cells from Scn8a mutant mice (Raman and Bean, 1997; Raman et al., 1997; Van Wart and Matthews, 2006; Aman and Raman, 2007). Reduced persistent and resurgent current was observed in several types of neurons by multiple investigators (Table ​(Table1).1). In addition to induced firing, spontaneous firing is reduced in Purkinje neurons isolated from null mice (Khaliq et al., 2003). Overall, the work summarized in Table ​Table11 demonstrates that Scn8a is a key determinant of neuronal excitability in vivo.

Original article before rough draft

Sodium channel, voltage gated, type VIII, alpha subunit also known as SCN8A or Nav1.6 is a protein which in humans is encoded by the SCN8A gene.[7] It is the primary voltage-gated sodium channel at the nodes of Ranvier. The channels are highly concentrated in sensory and motor axons in the peripheral nervous system and cluster at the nodes in the central nervous system. [8][9][10]

Structure edit

Nav1.6 is encoded by the SC8NA gene which contains 27 exons and measures 170 kb. The voltage gated sodium channel is composed of 1980 residues. Like other sodium channels, Nav1.6 is a monomer composed of four homologous domains and 25 transmembrane segments. SC8NA is regulated by exons 5N/5A and 18N/18A. 5N/5A and 18N/18A exons encode S3-S4 transmembrane segments that form an intracellular loop.

Function edit

Like other sodium channels, Nav1.6 facilitates action potential propagation when the membrane potential is depolarized by an influx of Na+ ions. However, the activation threshold of Nav1.6 is lower compared to other common sodium channels such as Nav1.2.[11] This feature allows Nav1.6 channels to rapidly recover from inactivation and sustain and high rate of activity.[12] The high frequency firing characteristic of Nav1.6 is caused by a persistent and resurgent sodium current. This characteristic is caused by slow activation of the sodium channel following depolarization,[13] which allows a steady-state sodium current after the initial action potential propagation. The steady-state sodium current contributes to the depolarization of the following action potential.

Clinical significance edit

Mutations in this gene have been associated to cases of early infantile epileptic encephalopathy.[14] The first known mutation in humans was a missense (c.5302A>G [p.Asn1768Asp]) mutation discovered by Krishna Veeramah and Michael Hammer.[15]

History edit

The SC8NA gene was identified in 1995 by John Caldwell in the rat,[16] and by Miriam Meisler in the mouse.[17]

John Caldwell in the rat,[18] and by Miriam Meisler in the mouse.[19]

See also edit

See also edit

  1. ^ a b Freeman SA, Desmazières A, Fricker D, Lubetzki C, Sol-Foulon N (February 2016). "Mechanisms of sodium channel clustering and its influence on axonal impulse conduction". Cellular and Molecular Life Sciences. 73 (4): 723–35. doi:10.1007/s00018-015-2081-1. PMC 4735253. PMID 26514731.
  2. ^ Chen, Yuan; Yu, Frank H.; Sharp, Elizabeth M.; Beacham, Daniel; Scheuer, Todd; Catterall, William A. (2016-11-08). "Functional Properties and Differential Neuromodulation of Nav1.6 Channels". Molecular and cellular neurosciences. 38 (4): 607–615. doi:10.1016/j.mcn.2008.05.009. ISSN 1044-7431. PMC 3433175. PMID 18599309.
  3. ^ Boiko T, Rasband MN, Levinson SR, Caldwell JH, Mandel G, Trimmer JS, Matthews G (April 2001). "Compact myelin dictates the differential targeting of two sodium channel isoforms in the same axon". Neuron. 30 (1): 91–104. PMID 11343647.
  4. ^ Veeramah KR, O'Brien JE, Meisler MH, Cheng X, Dib-Hajj SD, Waxman SG, Talwar D, Girirajan S, Eichler EE, Restifo LL, Erickson RP, Hammer MF (2012). "De novo pathogenic SCN8A mutation identified by whole-genome sequencing of a family quartet affected by infantile epileptic encephalopathy and SUDEP". American Journal of Human Genetics. 90 (3): 502–10. doi:10.1016/j.ajhg.2012.01.006. PMC 3309181. PMID 22365152.
  5. ^ Schaller KL, Krzemien DM, Yarowsky PJ, Krueger BK, Caldwell JH (1995). "A novel, abundant sodium channel expressed in neurons and glia". The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. 15 (5 Pt 1): 3231–42. PMID 7751906.
  6. ^ Burgess DL, Kohrman DC, Galt J, Plummer NW, Jones JM, Spear B, Meisler MH (1995). "Mutation of a new sodium channel gene, Scn8a, in the mouse mutant 'motor endplate disease'". Nature Genetics. 10 (4): 461–5. doi:10.1038/ng0895-461. PMID 7670495.
  7. ^ "Entrez Gene: SCN8A sodium channel, voltage gated, type VIII, alpha subunit".
  8. ^ Caldwell JH, Schaller KL, Lasher RS, Peles E, Levinson SR (May 2000). "Sodium channel Na(v)1.6 is localized at nodes of ranvier, dendrites, and synapses". Proceedings of the National Academy of Sciences of the United States of America. 97 (10): 5616–20. doi:10.1073/pnas.090034797. PMC 25877. PMID 10779552.
  9. ^ Boiko T, Rasband MN, Levinson SR, Caldwell JH, Mandel G, Trimmer JS, Matthews G (April 2001). "Compact myelin dictates the differential targeting of two sodium channel isoforms in the same axon". Neuron. 30 (1): 91–104. PMID 11343647.
  10. ^ Tzoumaka E, Tischler AC, Sangameswaran L, Eglen RM, Hunter JC, Novakovic SD (April 2000). "Differential distribution of the tetrodotoxin-sensitive rPN4/NaCh6/Scn8a sodium channel in the nervous system". Journal of Neuroscience Research. 60 (1): 37–44. doi:10.1002/(SICI)1097-4547(20000401)60:13.0.CO;2-W. PMID 10723066.
  11. ^ Freeman SA, Desmazières A, Fricker D, Lubetzki C, Sol-Foulon N (February 2016). "Mechanisms of sodium channel clustering and its influence on axonal impulse conduction". Cellular and Molecular Life Sciences. 73 (4): 723–35. doi:10.1007/s00018-015-2081-1. PMC 4735253. PMID 26514731.
  12. ^ Freeman SA, Desmazières A, Fricker D, Lubetzki C, Sol-Foulon N (2016). "Mechanisms of sodium channel clustering and its influence on axonal impulse conduction". Cellular and Molecular Life Sciences : CMLS. 73 (4): 723–35. doi:10.1007/s00018-015-2081-1. PMC 4735253. PMID 26514731.
  13. ^ Chen Y, Yu FH, Sharp EM, Beacham D, Scheuer T, Catterall WA (2008). "Functional properties and differential neuromodulation of Na(v)1.6 channels". Molecular and Cellular Neurosciences. 38 (4): 607–15. doi:10.1016/j.mcn.2008.05.009. PMC 3433175. PMID 18599309.
  14. ^ Vaher U, Nõukas M, Nikopensius T, Kals M, Annilo T, Nelis M, Ounap K, Reimand T, Talvik I, Ilves P, Piirsoo A, Seppet E, Metspalu A, Talvik T (December 2014). "De novo SCN8A mutation identified by whole-exome sequencing in a boy with neonatal epileptic encephalopathy, multiple congenital anomalies, and movement disorders". Journal of Child Neurology. 29 (12): NP202–6. doi:10.1177/0883073813511300. PMID 24352161.
  15. ^ Veeramah KR, O'Brien JE, Meisler MH, Cheng X, Dib-Hajj SD, Waxman SG, Talwar D, Girirajan S, Eichler EE, Restifo LL, Erickson RP, Hammer MF (March 2012). "De novo pathogenic SCN8A mutation identified by whole-genome sequencing of a family quartet affected by infantile epileptic encephalopathy and SUDEP". American Journal of Human Genetics. 90 (3): 502–10. doi:10.1016/j.ajhg.2012.01.006. PMC 3309181. PMID 22365152.
  16. ^ Schaller KL, Krzemien DM, Yarowsky PJ, Krueger BK, Caldwell JH (1995). "A novel, abundant sodium channel expressed in neurons and glia". The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. 15 (5 Pt 1): 3231–42. PMID 7751906.
  17. ^ Burgess DL, Kohrman DC, Galt J, Plummer NW, Jones JM, Spear B, Meisler MH (1995). "Mutation of a new sodium channel gene, Scn8a, in the mouse mutant 'motor endplate disease'". Nature Genetics. 10 (4): 461–5. doi:10.1038/ng0895-461. PMID 7670495.
  18. ^ Schaller KL, Krzemien DM, Yarowsky PJ, Krueger BK, Caldwell JH (1995). "A novel, abundant sodium channel expressed in neurons and glia". The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. 15 (5 Pt 1): 3231–42. PMID 7751906.
  19. ^ Burgess DL, Kohrman DC, Galt J, Plummer NW, Jones JM, Spear B, Meisler MH (1995). "Mutation of a new sodium channel gene, Scn8a, in the mouse mutant 'motor endplate disease'". Nature Genetics. 10 (4): 461–5. doi:10.1038/ng0895-461. PMID 7670495.
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