title: Inhibition of the GABA receptor-gated chloride ion channel in brain by noncompetitive inhibitors of the nicotinic receptor-gated cation channel.
abstract: 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.
authors: Department of Pharmacology, Duke University Medical Center, Durham, North Carolina.
authors: R D
authors: RD
authors: Schwartz
authors: M C
authors: MC
authors: Mindlin
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects*; D001643:Bridged Bicyclo Compounds / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002118:Calcium / Q000494:pharmacology; D018118:Chloride Channels; D002712:Chlorides; D066298:In Vitro Techniques; D007473:Ion Channels; D008297:Male; D008565:Membrane Proteins; D009118:Muscimol / Q000494:pharmacology; D010276:Parasympatholytics / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000187:drug effects*; D011978:Receptors, Nicotinic / Q000187:drug effects*; D014403:Tubocurarine / Q000494:pharmacology
chemical_list: D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018118:Chloride Channels; D002712:Chlorides; D007473:Ion Channels; D008565:Membrane Proteins; D010276:Parasympatholytics; D011963:Receptors, GABA-A; D011978:Receptors, Nicotinic; D009118:Muscimol; C046308:tert-butylbicyclo-2-benzoate; D002118:Calcium; D014403:Tubocurarine