Brain sodium channels

Molecularly, mammalian voltage-dependent sodium channels are composed of the main pore forming a subunit and smaller auxiliary (3 subunits. The rat brain sodium channel contains the 260-kD a subunit, the 36-kD (31 subunit and the 33-kD (32 subunit. The subunit stoichiometry is a (31 (32 = 1 1 1. 

Trainer VL, Moreau E, Guedin D, Baden DG, Catterall WA (1993) Neurotoxin binding and allosteric modulation at receptor sites 2 and 5 on purified and reconstituted rat brain sodium channels. JBiol Chem 268 17114—17119... 

Trainer VL, McPhee JC, Boutelet-Bochan H, Baker C, Scheuer T, Babin D, Demoute JP, Guedin D, Catterall WA (1997) High affinity binding of pyrethroids to the alpha subunit of brain sodium channels. Mol Pharmacol 51 651-657... 

When AP-A was treated with trypsin only the Argl4 to Glyl5 peptide bond was cleaved [56]. The resulting derivative lacked cardiotonic activity but its binding affinity for the rat brain sodium channel was reduced by less than an order of magnitude (Llewellyn LE et al., unpublished results). Its overall structure, as... 

Max M. B. and Flagen N. A. (2000). Do changes in brain sodium channels cause central pain Neurology 54 544-545. 

Smith RD, Goldin AL (1997) Phosphorylation at a single site in the rat brain sodium channel is necessary and sufficient for current reduction by protein kinase A. J Neurosci 77 6086-6093. 

Another field of application for sodium channel blockers is epilepsia. While epileptic seizures are a diverse and complex phenomenon, a key feature consists in bursts of excess excitatory activity of neurons in the brain. Sodium channel blockers will reduce nerve cell excitability, and they are thus one of the mainstays of anti-epileptic treatment. As but one example out of many. Figure 5.10 shows pheny-toin (or diphenylhydantoine). 

Ma JY, Catterall WA, Scheuer T 1997 Persistent sodium currents through brain sodium channels induced by G protein fSy subunits. Neuron 19 443-452... 

Isom LL, Ragsdale DS, De Jongh KS et al 1995a Structure and function of the /12 subunit of brain sodium channels, a transmembrane glycoprotein with a CAM motif. Cell 83 433—442 Isom LL, Scheuer T, Brownstein AB, Ragsdale DS, Murphy BJ, Catterall WA 1995b Functional... 

Li M, West JW, Lai Y, Scheuer T, CatteraU WA 1992 Functional modulation of brain sodium channels by cAMP-dependent phosphorylation. Neuron 8 1151-1159... 

Numann R, CatteraU WA, Scheuer T 1991 Functional modulation of brain sodium channels by protein kinase C phosphorylation. Science 254 115—118... 

Smith RD, Goldin AL 1996 Phosphorylation of brain sodium channels in the I—II linker modulates channel function in Xenopus oocytes. J Neurosci 16 1965-1974... 

Isom LL, De Jongh KS, Patton DE et al 1992 Primary structure and functional expression of the fii subunit of the rat brain sodium channel. Science 256 839-842... 

The S4 peptide and the IS2, IS4, IS34, IVS4 and Islink56 peptides of the rat brain sodium channel have been synthesized and studied in aqueous trifluoroethanol and DPC micelles using the NOE distance restraint/simulated annealing technique. All of the peptides were found to have predominantly a-helical structures in both types of environment. There was some evidence for bending of the longer helices but no discernible evidence for a well-defined tertiary structure. ... 

Catterall W A. Molecular properties of brain sodium channels an important target for anticonvulsant drugs. In Delgado-Escueta AV,Wilson WA, Olsen, RW, Porter RA, eds. Jasper s Masic Mechanisms of the Epilepsies, 3rded. Advances in Neurology, Vol. 79. Lippincott Williams Wilkins, Philadelphia, 1999, pp. 441-456. 

Effects of Pyrethroids on Mouse Brain Sodium Channels... 

We explored the potency of pyrethroid action in this system using deltamethrin, NRDC 157 (3-phenoxybenzyl [lR,cis]-3-( 2,2-dibromovinyl)-2,2-dimethylcyclopropanecarboxylate the non-cyano analog of deltamethrin), and their nontoxic enantiomers as test compounds ( Table II). Deltamethrin produced half-maximal enhancement of veratridine-dependent activation at 25 nM, whereas NRDC 157 was approximately tenfold less potent and the nontoxic enantiomers were inactive. These findings demonstrate that the effect of pyrethroids on mouse brain sodium channels is both potent and stereospecific for toxic isomers. The relative potencies of deltamethrin and NRDC 157 in this assay also agree well with their... 

Because altered sodium channels have been implicated in kdr and kdr-like resistance phenomena in insects, basic research on the biochemistry and molecular biology of this molecule, which plays a central role in normal processes of nervous excitation in animals, is of immediate relevance. The results of recent investigations of the voltage-sensitive sodium channels of vertebrate nerves and muscles have provided unprecedented insight into the structure of this large and complex membrane macromolecule. Sodium channel components from electric eel electroplax, mammalian brain, and mammalian skeletal muscle have been solubilized and purified (for a recent review, see Ref. 19). A large a subunit (ca. 2 60 kDa) is a common feature of all purified channels in addition, there is evidence for two smaller subunits ( Jl and J2 37-39 kDa) associated with the mammalian brain sodium channel and for one or two smaller subunits of similar size associated with muscle sodium channels. Reconstitution experiments with rat brain channel components show that incorporation of the a and pi subunits into phospholipid membranes in the presence of brain lipids or brain phosphatidylethanolamine is sufficient to produce all of the functional properties of sodium channels in native membranes (AA). Similar results have been obtained with purified rabbit muscle (45) and eel electroplax (AS.) sodium channels. 

Llewelly et al. compared the MBA for PSP toxins with four methods, including high performance liquid chromatography (HPLC) analysis, a commercial cell culture test, and RBAs performed with rat brain sodium channels and saxifilin. It was found that HPLC analysis had good correlation with RBAs and MBA, but HPLC estimated more toxicity than the MBA and RBAs underestimated toxicity as compared with MBA. 

Trainer, V. L., Baden, D. G., and Catterall, W. A., Identification of peptide components of the brevetoxin receptor site of rat brain sodium channels, J. Biol. Chem. 269, 19904, 1994. 

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