Ion Channel Pharmacology
Narahashi, T.
Neuroreceptors and ion channels as the basis for drug action: past, present, and future. The 200 ASPET Otto Krayer Award Lecture.
J. Pharmacol. Exp. Ther. 294: 1-26 (2000).
Hold, K. M. Sirisoma, N. S. Ikeda, T., Narahashi, T. and Casida, J. E.
Thujone (the active component of absinthe): -Aminobutyric acid type A receptor modulation and metabolic dotoxification.
Proc. Natl. Acad. Sci. USA 97: 3826-3831 (2000).
Motomura, H. and Narahashi, T.
Temperature dependence of pyrethroid modification of single sodium channels of rat hippocampal neurons.
J. Membrane Biol. 177: 23-39 (2000).
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Toshio Narahashi
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Our laboratory is engaged in extensive studies of nerve membrane ion channels using advanced electrophysiological techniques such as whole-cell and single-channel patch clamp. In addition to investigating fundamental properties of ion channels, we also study the roles ion channels play in the mechanism of action of drugs and environmental toxicants. Since our early discovery of the highly potent and specific blocking action of tetrodotoxin (puffer fish toxin) on the sodium channel, this toxin has become a popular chemical tool in the study of ion channels. Ion channels in the nervous system are the important target sites for a variety of therapeutic drugs and toxicants. Extensive studies are in progress in our laboratory to elucidate the mechanisms by which these chemicals modulate the function of various ion channels thereby causing therepeutic or toxic effects. Patch clamp techniques allow us to measure the activity of any types of ion channels with a high degree of precision, and when combined with molecular biology techniques, the molecular structure of ion channels that are responsible for drug modulation can be determined.
Our most recent studies of therapeutic drugs include alcohols, general anesthetics, nootropic drugs (cognitive enhancers), neuroprotective (anti-ischemic) drugs, and antiepileptic drugs. We previously demonstrated that alcohols and inhalational general anesthetics potentiate the GABAA receptor activity, and the mechanisms underlying this action are now being pursued. We have recently embarked on studies of neuronal nicotinic acetylcholine (ACh) receptors, andfound that both alcohols and general anesthetics modulate the ACh receptor activity in a complex and potent manner. This study is being extended to include the receptor subunit specificity using human embryonic kidney (HEK) cells in which various subunits are expressed. The ACh receptor study is also being extended to nootropic drugs as Alzheimer's disease is known to be associated with down regulation of the ACh receptor. Certain nootropic drugs potentiat the activity of the ACh receptor at subnanomolar concentrations (<10-9)via Gs proteins.
A variety of environmental toxicants have also been the subject of intense investigation in our laboratory. Our long-term studies of the pyrethroid insecticides have clearly established that they prolong the opening of the sodium channel thereby causing hyperactivity in animals and insects. We successfully measured how many sodium channels need to be modified by pyrethroids to produce hyperactivity; the number is astonishingly small, only about 1% of the sodium channel population. This accounts for the high potency of pyrethroids. Furthermore, the lower toxicity of pyrethroids in mammals as compared with the toxicity in insects can largely be explained by lower pyrethroid sensitivity of sodium channels in mammals than in insects. Detailed mechanisms of pyrethroid modulation of sodium channels are being analyzed by the single-channel patch clamp technique. The neuronal nicotinic ACh receptor has also been found to be the major target of imidacloprid, a new insecticide, and the selective toxicity between mammals and insects can be explained on the basis of differential sensitivities of the receptor.
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