Sodium channels molecular structure

Catterall WA (2000) From ionic currents to molecular mechanisms the structure and function of voltage-gated sodium channels. Neuron 26 13-25... 

Sir Henry Dale noticed that the different esters of choline elicited responses in isolated organ preparations which were similar to those seen following the application of either of the natural substances muscarine (from poisonous toadstools) or nicotine. This led Dale to conclude that, in the appropriate organs, acetylcholine could act on either muscarinic or nicotinic receptors. Later it was found that the effects of muscarine and nicotine could be blocked by atropine and tubocurarine, respectively. Further studies showed that these receptors differed not only in their molecular structure but also in the ways in which they brought about their physiological responses once the receptor has been stimulated by an agonist. Thus nicotinic receptors were found to be linked directly to an ion channel and their activation always caused a rapid increase in cellular permeability to sodium and potassium ions. Conversely, the responses to muscarinic receptor stimulation were slower and involved the activation of a second messenger system which was linked to the receptor by G-proteins. 

Class I— membrane stabilizing drugs to reduce cardiac electrical excitability molecules that are sodium channel blockers, usually based on local anesthetic molecular structure... 

Saxitoxin (32) is listed in Schedule 1 of the CWC. It is a polar, cationic, relatively low molecular mass toxin and is one of 18 structurally related neurotoxins collectively known as paralytic shellfish poisoning (PSP) toxins. Analogues are formed by addition of sulfate, A-sulfo and A-hydroxyl groups, and by decarbamylation. They block neuronal sodium channels, and thereby neurotransmission, death resulting from respiratory paralysis. Saxitoxin is produced by dinoflagellate species (and by some freshwater cyanobacteria), and accumulates in shellfish. The cationic nature of saxitoxin makes capillary electrophoresis combined with... 

Figure 7.5 Diagrammatic representation of the structure of a-subunit of vertebrate sodium channel showing the four internally homologous domains (I-IV), each containing six hydrophobic transmembrane helices. (From Soderlund, D.M., in Comprehensive Molecular Insect Science, Gilbert, L.I., Iatrou, K., and Gill, S.S., Eds., Vol. 5, Elsevier, London, 2005,1. With permission.)...

Pyrethroids are widely used to control many agriculturally and medically important insect pests. Due to intensive use of pyrethroids in pest control, many pest populations have developed resistance to these compounds. One major mechanism of pyrethroid resistance, conferred by the knock down resistance gene (Mr), is reduced target site (sodium channel) sensitivity to DDT and pyrethroids. Studies on the molecular basis of Mr and Mr-type resistance in various insects are enhancing our understanding of the structure and function of insect sodium channels and the molecular interaction between insect sodium channels and pyrethroids. In this chapter, I will review recent advances in... 

The best extractants in the above list of salts form complexes with the polyvalent metals that neutralize charges on the humic substances and link them to the inorganic soil colloids. These polyvalent ions are replaced by sodium ions from the salts. The efficiency of each solvent system will depend on the extent to which the resident cations are exchanged and removed from humic structures. Diffusion of the salts to the interior of solid humic substances is slow. Some channeling can take place, but extensive penetration would probably require the opening up from the outside of the macro-molecular structures. It would be necessary for these structures to remain open to allow exchange from the interior to take place. 

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. 

Comparative structural analysis of sodium channel genes has permitted the development of testable hypotheses concerning the neurotoxin recognition properties of the sodium channel protein. However, specific elements of the deduced structure have not yet been definitively correlated with the molecular recognition of sodium channel-directed neurotoxins by discrete binding domains. It is, thus, not possible at the present time to know which pharmacological properties are determined by the sodium channel protein per se and which are determined by interactions between it and crucial features of its membrane environment. Clearly, it will be necessary to analyze the effects of specific modifications of sodium channel structure in a defined membrane environment in order to address these and other questions relating to sodium channel function. 

The membrane ion channels are the molecular targets for several toxins that induce fast effects in cells. The chemical structure ofYTX [5-7] resembles those of brevetoxins and ciguatoxins, with more than ten contiguous ether rings. These two groups of toxins are fast and potent activators of voltagegated sodium channels, therefore some interaction of YTX with cellular ion channels could be expected. However, YTX did not interact with sodium channels and did not induce any competitive displacement of brevetoxins from site five of sodium channels [8]. 

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