Altered Sodium Channel Function

The molecular basis for the evolution of distinct kdr mutations in different insects and arachnids remains unclear. Assuming that the pyrethroid binding site(s) (and/or the pyrethroid response domain) is composed of multiple amino acid residues, there are two ways by which different mutations can be selected in different insects and arachnids. First, the random mutation hypothesis mutation in any pyrethroid binding site/response domain affects pyrethroid toxicity without impacting normal sodium channel functional properties. Thus, selection of different mutations in different insects and arachnids is purely random. Second, the nonrandom mutation hypothesis mutation in any pyrethroid binding site/response domain affects pyrethroid toxicity, but some mutations also drastically alter normal sodium channel functional properties in one species, but not in another, presumably because of different sodium channel backbone sequences. That is, there may be severe fimess costs for some mutations, if placed out of their native protein context. 

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. 

A subset of ion channels not gated by traditional neurotransmitters represents another receptor class. These iaclude potassium, calcium, sodium, and cychc adenosiae monophosphate (cAMP)-gated channels (14—16) for which a large number of synthetic molecules exist that alter ceUular function. 

Recently, Cl" channels have been discovered. These channels have no sequence relationship to the voltage-gated Na, and Ca channels. One such channel is involved in the disease, cystic fibrosis. In this disease, regulation of the channel is defective. The altered function of the channel in epithelia causes elevated levels of sodium and chloride ions in sweat and, through unknown processes, the accumulation of mucus in the respiratory tract and failure of exocrine secretion in glands, such as the pancreas. Blockage of airways leads to chronic lung infections that, with other effects of the Cl" transport deficiency, can be fatal. 

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