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

Publication ,  Journal Article
Schwartz, RD; Mindlin, MC
Published in: J Pharmacol Exp Ther
March 1988

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.

Duke Scholars

Published In

J Pharmacol Exp Ther

ISSN

0022-3565

Publication Date

March 1988

Volume

244

Issue

3

Start / End Page

963 / 970

Location

United States

Related Subject Headings

  • Tubocurarine
  • Receptors, Nicotinic
  • Receptors, GABA-A
  • Rats, Inbred Strains
  • Rats
  • Pharmacology & Pharmacy
  • Parasympatholytics
  • Muscimol
  • Membrane Proteins
  • Male
 

Published In

J Pharmacol Exp Ther

ISSN

0022-3565

Publication Date

March 1988

Volume

244

Issue

3

Start / End Page

963 / 970

Location

United States

Related Subject Headings

  • Tubocurarine
  • Receptors, Nicotinic
  • Receptors, GABA-A
  • Rats, Inbred Strains
  • Rats
  • Pharmacology & Pharmacy
  • Parasympatholytics
  • Muscimol
  • Membrane Proteins
  • Male