Neuroreceptors and ion channels as the basis for drug action: past, present, and future.
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 of N-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 alpha-bungarotoxin-insensitive, alpha4beta2-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 gamma-aminobutyric acid(A) receptors and inhibit the activity of alpha4beta2-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 how changes in the molecular structure of drugs and receptors/channels result in kinetic changes in the function of receptors/channels.
Narahashi
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Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School, Chicago, Illinois 60611, USA. tna597@anima.nums.nwu.edu
D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D007473:Ion Channels / Q000187:drug effects*; D009420:Nervous System / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D011722:Pyrethrins / Q000633:toxicity; D011963:Receptors, GABA-A / Q000187:drug effects*; D011978:Receptors, Nicotinic / Q000187:drug effects*; D012530:Saxitoxin / Q000633:toxicity; D013779:Tetrodotoxin / Q000633:toxicity
D000779:Anesthetics, Local; D007473:Ion Channels; D018696:Neuroprotective Agents; D011722:Pyrethrins; D011963:Receptors, GABA-A; D011978:Receptors, Nicotinic; D012530:Saxitoxin; D013779:Tetrodotoxin