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OrationTHE 2000 ASPET OTTO KRAYER AWARD LECTURE

Neuroreceptors and Ion Channels as the Basis for Drug Action: Past, Present, and Future

Toshio Narahashi
Journal of Pharmacology and Experimental Therapeutics July 2000, 294 (1) 1-26;
Toshio Narahashi
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Abstract

This article summarizes the development of cellular neuropharmacology and neurotoxicology, based primarily on my own research. The progress of this field depends at least in part on the theoretical and technological developments of excitable cell physiology, biophysics, and biochemistry. First, a brief historical development is described. Second, my earlier studies of the mechanism of action of insecticides on the nervous system are introduced. The most significant is the early discovery of the increase in depolarizing after-potential caused by DDT and pyrethroids. This laid the foundation of subsequent analyses of sodium channel modulation as the major mechanism of action of DDT/pyrethroids. Third, my initial contributions to cellular neuropharmacology are described. The discovery of the potent and selective block of sodium channels by tetrodotoxin aroused interest not only in using this toxin and other chemicals as useful laboratory tools but also in studying receptors/channels as important targets of various drugs. Using internally perfused squid giant axons, pioneering studies of local anesthetic action led to the conclusion that these anesthetics block the sodium channel from inside the nerve membrane in the cationic form. Fourth, a few examples of my more recent studies using voltage-clamp and patch-clamp techniques are described. Pyrethroid modulation of sodium channels was analyzed in great detail, including single-channel kinetics, toxicity amplification from channels to animal behaviors, temperature dependence, selective toxicity, and vitamin E antagonism. The neuroprotective drug riluzole blocked sodium channels and high-voltage-activated calcium channels, thereby preventing excess stimulation ofN-methyl-d-aspartate receptors and massive influx of calcium, thereby retarding spread of infarction in the brain. Neuronal nicotinic acetylcholine receptors have received much attention recently, and I launched an extensive study of the mechanism whereby alcohols and general anesthetics modulate their activity. Ethanol potently stimulates the α-bungarotoxin-insensitive, α4β2-type acetylcholine receptors, thereby causing release of various transmitters; this leads to a cascade of multisynaptic events and behavioral changes. Inhalational general anesthetics augment the activity of γ-aminobutyric acidA receptors and inhibit the activity of α4β2-type acetylcholine receptors, causing a variety of clinical syndromes. Fifth, one of the possible future directions of cellular neuropharmacology and neurotoxicology is discussed. Emphasis is placed on the three-dimensional structure-activity relationship, in particular howchanges in the molecular structure of drugs and receptors/channels result in kinetic changes in the function of receptors/channels.

Footnotes

  • Send reprint requests to: Dr. Toshio Narahashi, Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School, 303 E. Chicago Ave., Chicago, IL 60611. E-mail: tna597{at}anima.nums.nwu.edu

  • ↵1 The recent work in this article was supported by National Institutes of Health Grants NS14143, NS14144, and AA07836.

  • Abbreviations:
    MBL
    Marine Biological Laboratory
    NMDA
    N-methyl-d-aspartate
    TTX
    tetrodotoxin
    STX
    saxitoxin
    TTX-R
    TTX-resistant
    DRG
    dorsal root ganglion
    TTX-S
    TTX-sensitive
    BTX
    batrachotoxin
    GTX
    grayanotoxin
    HVA
    high voltage-activated
    AChR
    acetylcholine receptor
    nAChR
    nicotinic AChR
    nnAChR
    neuronal nAChR
    α-BuTX
    α-bungarotoxin
    EPC
    end-plate current
    SAR
    structure-activity relationship
    GABA
    γ-aminobutyric acid
    • Received April 12, 2000.
    • Accepted April 13, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 294 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 294, Issue 1
1 Jul 2000
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OrationTHE 2000 ASPET OTTO KRAYER AWARD LECTURE

Neuroreceptors and Ion Channels as the Basis for Drug Action: Past, Present, and Future

Toshio Narahashi
Journal of Pharmacology and Experimental Therapeutics July 1, 2000, 294 (1) 1-26;

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OrationTHE 2000 ASPET OTTO KRAYER AWARD LECTURE

Neuroreceptors and Ion Channels as the Basis for Drug Action: Past, Present, and Future

Toshio Narahashi
Journal of Pharmacology and Experimental Therapeutics July 1, 2000, 294 (1) 1-26;
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