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γ-Aminobutyric acid (GABA)- and barbiturate-mediated 36Cl-uptake in rat brain synaptoneurosomes: Evidence for rapid desensitization of the GABA receptor-coupled chloride ion channel

Publication ,  Journal Article
Schwartz, RD; Suzdak, PD; Paul, SM
Published in: Molecular Pharmacology
December 1, 1986

'Desensitization' of the γ-aminobutyric acid (GABA) receptor-coupled chloride ion channel was studied using an in vitro method for measuring chloride (Cl-) permeability in brain vesicles (synaptoneurosomes). Muscimol, a GABA agonist, stimulated 36Cl-uptake in rat cerebral cortical synaptoneurosomes in a concentration-dependent manner (EC50 7.3 ± 0.5 μM), whereas pentobarbital stimulated 36Cl- uptake in a biphasic manner, indicated by a bell-shaped concentration-response relationship, with a maximal response at 500 μM (EC50 271 ± 17 μM). Higher concentrations of pentobarbital led to progressively smaller stimulation of 36Cl- uptake and blocked muscimol-stimulated 36Cl- uptake. Lower concentrations of pentobarbital (100-200 μM), when added with muscimol, produced an additive effect in stimulating 36Cl- uptake, whereas even lower (subthreshold) concentrations of pentobarbital (50 μM) potentiated muscimol-stimulated 36Cl- uptake. Following continuous exposure of synaptoneurosomes (up to 20 min) to muscimol (50 μM) or pentobarbital (500 μM), the 36Cl- uptake response diminished to a new steady state level with a t1 of ~6 sec and 30 sec, respectively. The decrement in response to these agonists was dependent on both concentration and length of exposure. No decrement was observed in the ability of subthreshold concentrations of pentobarbital to enhance muscimol-stimulated 36Cl- uptake following prolonged (20 min) incubation. 'Heterologous desensitization' between muscimol and pentobarbital was observed in experiments where either muscimol or pentobarbital was added to the vesicles following pretreatment with the other. These findings suggest that 'desensitization' of the GABA receptor/Cl- ion channel may involve both the GABA and barbiturate recognition sites or a common effector component such as the ionophore itself.

Duke Scholars

Published In

Molecular Pharmacology

ISSN

0026-895X

Publication Date

December 1, 1986

Volume

30

Issue

5

Start / End Page

419 / 426

Related Subject Headings

  • Pharmacology & Pharmacy
  • 3214 Pharmacology and pharmaceutical sciences
  • 3101 Biochemistry and cell biology
  • 1115 Pharmacology and Pharmaceutical Sciences
  • 1109 Neurosciences
  • 0601 Biochemistry and Cell Biology
 

Published In

Molecular Pharmacology

ISSN

0026-895X

Publication Date

December 1, 1986

Volume

30

Issue

5

Start / End Page

419 / 426

Related Subject Headings

  • Pharmacology & Pharmacy
  • 3214 Pharmacology and pharmaceutical sciences
  • 3101 Biochemistry and cell biology
  • 1115 Pharmacology and Pharmaceutical Sciences
  • 1109 Neurosciences
  • 0601 Biochemistry and Cell Biology