| Literature References | 1. GEORGE, A.L., KNITTLE, T.J. AND TAMKUN, M.M.
Molecular cloning of an atypical voltage-gated sodium channel expressed in
human heart and uterus - Evidence for a distinct gene family.
PROC.NATL.ACAD.SCI.U.S.A. 89(11) 4893-4897 (1992).
2. NODA, M., IKEDA, T., KAYANO, T., SUZUKI, H., TAKESHIMA, H.,
KURASAKI, M., TAKAHASHI, H. AND NUMA, S.
Existence of distinct sodium channel messenger RNAs in rat brain.
NATURE 320 188-192 (1986).
3. NODA, M., SHIMIZU, S., TANABE, T., TAKAI, T., KAYANO, T., IKEDA, T.,
TAKAHASHI, H., NAKAYAMA, H., KANAOKA, Y., MINAMINO, M., KANGAWA, K.,
MATSUO, H., RAFTERY, M.A., HIROSE, T., INAYAMA, S., HAYASHIDA, H,
MIYATA, T. AND NUMA, S.
Primary structure of Electrophorus electricus sodium channel deduced from
cDNA sequence.
NATURE 312 121-127 (1984).
4. ROGART, R.B., CRIBBS, L.L., MUGLIA, L.K., KEPHART, D.D. AND KAISER, M.W.
Molecular cloning of a putative tetrodotoxin resistant rat heart Na+
channel isoform.
PROC.NATL.ACAD.SCI.U.S.A. 86(20) 8170-8174 (1989).
5. SATO, C. AND MATSUMOTO, G.
Proposed tertiary structure of the sodium channel.
BIOCHEM.BIOPHYS.RES.COMMUN. 186 1158-1167 (1992).
6. BRAMMER, W.J.
VLG Na (Voltage-gated sodium channels).
IN THE ION CHANNEL FACTSBOOK VOLUME IV, ACADEMIC PRESS, 1999, PP.768-838.
7. ABOU-KHALIL,B., GE, Q., DESAI, R., RYTHER, R., BAZYK, A., BAILEY, R.,
HAINES, J.L., SUTCLIFFE, J.S. AND GEORGE, A.L.
Partial and generalized epilepsy with febrile seizures plus and a novel
SCN1A mutation.
NEUROLOGY 26 57(12) 2265-2272 (2001).
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| Documentation | Voltage-dependent sodium channels are transmembrane (TM) proteins
responsible for the depolarising phase of the action potential in most
electrically excitable cells [1]. They may exist in 3 states [3]: the
resting state, where the channel is closed; the activated state, where the
channel is open; and the inactivated state, where the channel is closed
and refractory to opening. Several different structurally and functionally
distinct isoforms are found in mammals, coded for by a multigene family
[4], these being responsible for the different types of sodium ion currents
found in excitable tissues.
The structure of sodium channels is based on 4 internal repeats of a 6-helix
bundle [2] (in which 5 of the membrane-spanning segments are hydrophobic and
the other is positively charged), forming a 24-helical bundle. The charged
segments are believed to be localised within clusters formed by their 5
hydrophobic neighbours: it is postulated that the charged domain may be the
voltage sensor region, possibly moving outward on depolarisation, causing a
conformational change. This model, proposed by Noda et al. [2], contrasts
with that of Sato and Matsumoto [5], in which the TM segments are juxtaposed
octagonally. The basic structural motif (the 6-helix bundle) is also found
in potassium and calcium channel alpha subunits.
The SCN1A gene encodes the NaB1 channel and is particularly expressed in
the brain, but is also found in a variety of other tissues, ranging from the
retina to the olfactory bulb [6]. Epilepsy, a disorder of neuronal
hyperexcitability, has been associated with altered kinetics of SCN1A, as
well as delayed inactivation of SCN2A [7].
NACHANNEL1 is a 4-element fingerprint that provides a signature for the
voltage-gated Na+ channel alpha 1 subunit. The fingerprint was derived from
an initial alignment of 3 sequences: the motifs were drawn from conserved
regions spanning the N-terminal third of the alignment, focusing on those
sections that characterise the alpha 1 subunits but distinguish them from
the rest of the voltage-gated Na+ channel superfamily - motifs 1 and 2
reside in the loop between TM domains 5 and 6 in the first repeat; and
motifs 3 and 4 lie in the C-terminus of the fourth repeat. A single
iteration on SPTR40_18f was required to reach convergence, no further
sequences being identified beyond the starting set.
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