Inhibition of the GABA receptor-gated chloride ion channel in brain by noncompetitive inhibitors of the nicotinic receptor-gated cation channel.

Article date: 1988/3/1

PubMed ID: 2472481

Journal name: The Journal of pharmacology and experimental therapeutics (ISSN: 0022-3565)


The ability of various noncompetitive inhibitors (NCI) of the nicotinic acetylcholine receptor to inhibit gamma-aminobutyric acidA (GABA) receptor activity in brain was investigated. Micromolar concentrations of NCI such as tetraphenylphosphonium, mepacrine, chlorpromazine and phencyclidine inhibited muscimol-induced 36chloride (36Cl-) uptake in rat cerebral cortical synaptoneurosomes in a noncompetitive manner. D-Tubocurarine behaved as a competitive inhibitor. In experiments measuring the time course of muscimol-induced 36Cl- uptake, a decline in the apparent transport rate constant (k') (reflection of desensitization) occurred over the first 3 sec. At lowered temperature (22 degrees C) the k' did not decline during the first 4 sec. Under these conditions preincubation of the vesicles with tetraphenylphosphonium caused a marked decline in the apparent k' over the first 5 sec (transition T1/2 of 1.04 sec) suggesting that tetraphenylphosphonium promotes desensitization of the GABA receptor. The inhibition of muscimol-induced 36Cl- uptake by NCI was reduced in the absence of Ca++. In addition, Ca++ decreased the potency of muscimol to stimulate 36Cl- uptake with an IC50 = 64 microM. The interaction of NCI with GABA agonist and convulsant sites associated with the GABA receptor-gated Cl- channel also was investigated. NCI antagonized noncompetitively [3H]t-butylbicycloorthobenzoate binding to convulsant sites whereas only mepacrine and chlorpromazine antagonized binding of [3H]muscimol to agonist sites. These findings suggest that 1) inhibition of the GABA receptor-gated Cl- channel by NCI may explain the convulsant properties of several of these compounds and 2) there may be structural domains common to the GABA receptor and nicotinic receptor-gated ion channels that selectively permit interactions with various NCI.

This document is available from: http://directlinks.cc/files/muscimol/2472481.pdf

Author List: Schwartz R D, Mindlin M C

Publication Types: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.

Substances mentioned in the article: Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Chloride Channels; Chlorides; Ion Channels; Membrane Proteins; Parasympatholytics; Receptors, GABA-A; Receptors, Nicotinic; Muscimol; tert-butylbicyclo-2-benzoate; Calcium; Tubocurarine;

Mesh terms: Animals; Brain/drug effects; Bridged Bicyclo Compounds/metabolism; Bridged Bicyclo Compounds, Heterocyclic; Calcium/pharmacology; Chloride Channels; Chlorides; In Vitro Techniques; Ion Channels; Male; Membrane Proteins; Muscimol/pharmacology; Parasympatholytics/pharmacology; Rats; Rats, Inbred Strains; Receptors, GABA-A/drug effects; Receptors, Nicotinic/drug effects; Tubocurarine/pharmacology;

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