Nav1.1
Description: sodium channel, voltage-gated, type I, alpha Gene: Scn1a Synonyms: nav1.1, scn1a1
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
Gene
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 | |
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]
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].
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].
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].
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
Model
Nav1.1 Hodgkin–Huxley type conductance-based models of spiking neurons were constructed using the NEURON program. [37]
References
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Calmodulin and calcium differentially regulate the neuronal Nav1.1 voltage-dependent sodium channel.
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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]