Nav1.1

Description: sodium channel, voltage-gated, type I, alpha
Gene: Scn1a Synonyms: nav1.1, scn1a1

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Introduction

Nav1.1, also known as the sodium channel, voltage-gated, type I, alpha subunit (SCN1A), is a protein which in humans is encoded by the SCN1A gene.

The vertebrate sodium channel is a voltage-gated ion channel essential for the generation and propagation of action potentials, chiefly in nerve and muscle. Voltage-sensitive sodium channels are heteromeric complexes consisting of a large central pore-forming glycosylated alpha subunit and 2 smaller auxiliary beta subunits. Functional studies have indicated that the transmembrane alpha subunit of the brain sodium channels is sufficient for expression of functional sodium channels. Brain sodium channel alpha subunits form a gene subfamily with several structurally distinct isoforms clustering on chromosome 2q24, types I, II (Nav1.2), and III (Nav1.3). There are also several distinct sodium channel alpha subunit isoforms in skeletal and cardiac muscle (Nav1.4 and Nav1.5 respectively).

From http://en.wikipedia.org/wiki/Nav1.1

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Gene

RGD ID	Chromosome	Position	Species
69364	3	48238528-48364143	Rat
735778	2	66108839-66278894	Mouse
735777	2	166845670-166930149	Human

Scn1a : sodium channel, voltage-gated, type I, alpha

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Transcript

Acc No	Sequence	Length	Source
NM_030875	n/A	n/A	NCBI
NM_018733	n/A	n/A	NCBI
NM_006920	n/A	n/A	NCBI
NM_001165963	n/A	n/A	NCBI
NM_001165964	n/A	n/A	NCBI
NM_001202435	n/A	n/A	NCBI

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Ontology

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Interaction

Calmodulin and Ca++ Concentration

Nav1.1 can be regulated by CaM and by Ca++ alone, and these effectors may antagonize each other. The regulation by Ca++ is likely to involve the direct interaction of Ca++ ions with the Nav1.1 C-terminal region. [482]

FGF

Fibroblast Growth Factor Homologous Factors (FHF1-4) modulate sodium channels in an isoform-dependent manner. In fact, FHF4 (B isoform) reduces current density by 90% of Nav1.1. [1372]

Neurotransmitters

NaV1.1 are regulated by neutrottransmiters that act through G-protein coupled receptors and activate protein kinase A such dopamine, acetylcholine and serotonin (reviewed in Cantrell & Catterall, 2001). [1386]

Tetrodotoxin

Nav1.1 is TTX sensitive [1376]

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Protein

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Structure

Nav1.1 is a 260 kDa transmembrane protein with four homologous domains (D1 to D4) that comprises the pore-forming alpha subunit of a voltage-gated sodium channel. The alpha subunit is associated with one or more beta subunits in different tissues. Each domain of the alpha subunit contains six transmembrane segments (S1 to S6). The S4 segment of each domain is responsible for conferring the voltage-gating properties of the channel. To date, 4 of the 15 SCN1A GEFS+ mutations have been located in S4 segments, confirming the importance of this domain in channel function.[38]. (Figure 1 in [40] sketches the structure of the Nav1.1 channel).
The cytoplasmic loop that connect domains II and III of the Nav1 subunit contains a determinant conferring compartmentalization in the axonal initial segment of rat hippocampal neurons. Expression of a soluble Nav1.2II-III linker protein led to the disorganization of endogenous sodium channels. The motif was sufficient to redirect a somatodendritic potassium channel to the axonal initial segment, a process involving association with ankyrin G. Thus, this motif may play a fundamental role in controlling electrical excitability during development and plasticity [408].

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Distribution

Nav1.1 are present in neurons and glia [834]. The Nav1.1 polypeptide was found predominantly in the cell bodies and dendrites of expressing cells [1370]. Nav1.1 channels are presumably involved in propagating synaptic signals from dendrites to soma and in integration of electrical signals within the soma prior to the initiation of axonal action potentials [1368]. In fact, NaV1.1 is the primary voltage-gated Na+ channel in several clases of GABAergic interneurons, and its reduced activity leads to reduced excitability and decreased GABAergic tone [1369]; in fact, loss of NaV1.1 channels in forebrain GABAergic neurons is both necessary and sufficient to cause epilepsy and premature death in Dravet Syndrome [1384]. Moreover, Nav1.1 distribution is concentrated in a axonal initial segment subcompartment in spinal cord neurons including 80% of motor neurons and in multiple brain areas and this expression suggest that is is involved in the control of action potential generation and propagation [366].

In the adult rat and human hippocampus, strong Nav1.1 staining is present on the soma of dentate granule cells and of interneurons dispersed throughout the dentate hilus. Intense staining is also seen in stratum pyramidale of all hippocampal subfields (CA1, CA2, and CA3) with staining restricted to the pyramidal cell somata and proximal dendrites [1368].

Robust Nav1.1 staining is also observed on the soma and apical dendrites of pyramidal cells in layer V of the cerebral cortex. In the cerebellum, granule cells and Purkinje cells have strong Nav1.1 staining on the soma, and clear staining is seen on Purkinje cell dendrites. It should be noted that strikingly similar patterns of Nav1.1 staining were observed in human brain [1371], suggesting that this distinct pattern of localization is evolutionarily conserved and that somatodendritic targeting of Nav1.1 is essential for normal response properties across species [1368].

The also appears to control the polarized localization of Nav channels in neurons. As C-terminal cytoplasmic domain (CLDILFAFT) was identified that mediates both axonal targeting and somato dendritic endocytosis of Nav1.1. It has been also identified a second Nav1 targeting determinant that directs localization of these channels to the axon initial segment [1368].

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Expression

Nav1.1 expression increases during the third postnatal week and peaks at the end of the first postnatal month, after which levels decrease by about 50% in the adult. Specifically, Nav1.1 was detected at high levels in the hippocampus (CA1, CA2, CA3, and additional staining is present in a subpopulation of interneurons dispersed throughout s. radiatum and s. oriens. [1368]), cerebellum (Purkinje cells but not in granule cells [834]), spinal cord, brainstem, cortex, substantia nigra, and caudate. Recently, NaV1.1 channels are expressed in the suprachiasmatic nucleus (SCN) of the hypothalamus [1369]. Regarding to the PNS, Nav1.1 is present at high levels in DRG and in nodes of Ranvier throughout the mouse spinal cord [834], [366].

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Functional

Loss-of-function mutations of NaV1.1 channels cause severe channelopathies:

+ Epilepsy [1373]
+ Febrile epilepsy [1373]
+ Generalized epilepsy with febrile seizure (GEFS+)[1373]
+ Dravet syndrome [1373]
+ Doose syndrome [1374]
+ Rasmussen's encephalitis [1375]
+ Lennox-Gastaut syndrome [1376]
+ Familial hemiplegic migraine (FHM)[1377]
+ Familial autism [1378]
+ Panayiotopoulos syndrome [1379]
+ Mutations catalog [1380]

SCN1A alterations are also related with Alzheimer [1381] and migraine with aura [39].

Mice models

Scn1a+/- (Dravet's syndrome) [1382]
Scn1a+/- (SMEI) [1383]

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Kinetics

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Model

Nav1.1 Hodgkin–Huxley type conductance-based models of spiking neurons were constructed using the NEURON program. [37]

References

Kalume F et al. Reduced sodium current in Purkinje neurons from Nav1.1 mutant mice: implications for ataxia in severe myoclonic epilepsy in infancy.
J. Neurosci., 2007 Oct 10 , 27 (11065-74).

Spampanato J et al. Increased neuronal firing in computer simulations of sodium channel mutations that cause generalized epilepsy with febrile seizures plus.
J. Neurophysiol., 2004 May , 91 (2040-50).

Barela AJ et al. An epilepsy mutation in the sodium channel SCN1A that decreases channel excitability.
J. Neurosci., 2006 Mar 8 , 26 (2714-23).

Cestèle S et al. Self-limited hyperexcitability: functional effect of a familial hemiplegic migraine mutation of the Nav1.1 (SCN1A) Na+ channel.
J. Neurosci., 2008 Jul 16 , 28 (7273-83).

Rusconi R et al. Modulatory proteins can rescue a trafficking defective epileptogenic Nav1.1 Na+ channel mutant.
J. Neurosci., 2007 Oct 10 , 27 (11037-46).

330

Ogiwara I et al. Na(v)1.1 localizes to axons of parvalbumin-positive inhibitory interneurons: a circuit basis for epileptic seizures in mice carrying an Scn1a gene mutation.
J. Neurosci., 2007 May 30 , 27 (5903-14).

481

Leipold E et al. Combinatorial interaction of scorpion toxins Lqh-2, Lqh-3, and LqhalphaIT with sodium channel receptor sites-3.
Mol. Pharmacol., 2004 Mar , 65 (685-91).

482

Gaudioso C et al. Calmodulin and calcium differentially regulate the neuronal Nav1.1 voltage-dependent sodium channel.
, 2011 Jun 25 , ().

1369

Han S et al. Na(V)1.1 channels are critical for intercellular communication in the suprachiasmatic nucleus and for normal circadian rhythms.
Proc. Natl. Acad. Sci. U.S.A., 2012 Feb 7 , 109 (E368-77).

366

Duflocq A et al. Nav1.1 is predominantly expressed in nodes of Ranvier and axon initial segments.
Mol. Cell. Neurosci., 2008 Oct , 39 (180-92).

1368

Trimmer JS et al. Localization of voltage-gated ion channels in mammalian brain.
Annu. Rev. Physiol., 2004 , 66 (477-519).

1370

Westenbroek RE et al. Differential subcellular localization of the RI and RII Na+ channel subtypes in central neurons.
Neuron, 1989 Dec , 3 (695-704).

1371

Whitaker WR et al. Distribution of voltage-gated sodium channel alpha-subunit and beta-subunit mRNAs in human hippocampal formation, cortex, and cerebellum.
J. Comp. Neurol., 2000 Jun 19 , 422 (123-39).

1372

Lou JY et al. Fibroblast growth factor 14 is an intracellular modulator of voltage-gated sodium channels.
J. Physiol. (Lond.), 2005 Nov 15 , 569 (179-93).

1373

Escayg A et al. Sodium channel SCN1A and epilepsy: mutations and mechanisms.
Epilepsia, 2010 Sep , 51 (1650-8).

1374

Yordanova I et al. One novel Dravet syndrome causing mutation and one recurrent MAE causing mutation in SCN1A gene.
Neurosci. Lett., 2011 Apr 25 , 494 (180-3).

1375

Ohmori I et al. Rasmussen encephalitis associated with SCN 1 A mutation.
Epilepsia, 2008 Mar , 49 (521-6).

1376

Savio-Galimberti E et al. Voltage-gated sodium channels: biophysics, pharmacology, and related channelopathies.
Front Pharmacol, 2012 , 3 (124).

1377

Kahlig KM et al. Divergent sodium channel defects in familial hemiplegic migraine.
Proc. Natl. Acad. Sci. U.S.A., 2008 Jul 15 , 105 (9799-804).

1378

Weiss LA et al. Sodium channels SCN1A, SCN2A and SCN3A in familial autism.
Mol. Psychiatry, 2003 Feb , 8 (186-94).

1379

Grosso S et al. SCN1A mutation associated with atypical Panayiotopoulos syndrome.
Neurology, 2007 Aug 7 , 69 (609-11).

1380

Lossin C A catalog of SCN1A variants.
Brain Dev., 2009 Feb , 31 (114-30).

1381

Verret L et al. Inhibitory interneuron deficit links altered network activity and cognitive dysfunction in Alzheimer model.
Cell, 2012 Apr 27 , 149 (708-21).

1382

Han S et al. Autistic-like behaviour in Scn1a+/- mice and rescue by enhanced GABA-mediated neurotransmission.
Nature, 2012 Sep 20 , 489 (385-90).

1383

Yu FH et al. Reduced sodium current in GABAergic interneurons in a mouse model of severe myoclonic epilepsy in infancy.
Nat. Neurosci., 2006 Sep , 9 (1142-9).

1384

Cheah CS et al. Specific deletion of NaV1.1 sodium channels in inhibitory interneurons causes seizures and premature death in a mouse model of Dravet syndrome.
Proc. Natl. Acad. Sci. U.S.A., 2012 Sep 4 , 109 (14646-51).

1386

Cantrell AR et al. Neuromodulation of Na+ channels: an unexpected form of cellular plasticity.
Nat. Rev. Neurosci., 2001 Jun , 2 (397-407).

408

Garrido JJ et al. A targeting motif involved in sodium channel clustering at the axonal initial segment.
Science, 2003 Jun 27 , 300 (2091-4).

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Credits

Contributors: Rajnish Ranjan, Michael Schartner

To cite this page: [Contributors] Channelpedia https://channelpedia.epfl.ch/ionchannels/120/ , accessed on [date]