GAMMA-AMINOBUTYRIC-ACID (GABA)-MEDICATED AND BARBITURATE-MEDIATED CL-36(-) UPTAKE IN RAT-BRAIN SYNAPTONEUROSOMES - EVIDENCE FOR RAPID DESENSITIZATION OF THE GABA RECEPTOR-COUPLED CHLORIDE-ION CHANNEL
- 1 November 1986
- journal article
- research article
- Vol. 30 (5), 419-426
Abstract
"Desensitization" of the .gamma.-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 .mu.M), whereas pentobarbital stimulated 36Cl- uptake in a biphasic manner, indicated by a bell-shaped concentration-response relationship, with a maximal response at 500 .mu.M (EC50 271 .+-. 17 .mu.M). Higher concentrations of pentobarbital led to progressively smaller stimulation of 36Cl- uptake and blocked muscimol-stimulated 36Cl- uptake. Lower concentrations of pentobarbital (100-200 .mu.M), when added with muscimol, produced an additive effect in stimulating 36Cl- uptake, whereas even lower (subthreshold) concentrations of pentobarbital (50 .mu.M) potentiated muscimol-stimulated 36Cl- uptake. Following continuous exposure of synaptoneurosomes (up to 20 min) to muscimol (50 .mu.M) or pentobarbital (500 .mu.M), the 36Cl- uptake response diminished to a new steady state leel with a t1/2 of .apprx. 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.This publication has 30 references indexed in Scilit:
- THE BENZODIAZEPINE - GABA - CHLORIDE IONOPHORE RECEPTOR COMPLEX - COMMON SITE OF MINOR TRANQUILIZER ACTION1981
- Barbiturate receptor sites are coupled to benzodiazepine receptors.Proceedings of the National Academy of Sciences, 1980
- Enhancement of GABA binding by pentobarbitoneNeuroscience Letters, 1980
- The effects of pentobarbital and related compounds on frog motoneuronsBrain Research, 1980
- Amino acid pharmacology of mammalian central neurones grown in tissue culture.The Journal of Physiology, 1978
- Pentobarbitone pharmacology of mammalian central neurones grown in tissue culture.The Journal of Physiology, 1978
- Interaction of barbiturates with dihydropicrotoxinin binding sites related to the GABA receptor-ionophore systemLife Sciences, 1978
- BINDING OF (H-3)ALPHA-DIHYDROPICROTOXININ, A GAMMA-AMINOBUTYRIC ACID SYNAPTIC ANTAGONIST, TO RAT-BRAIN MEMBRANES1978
- Barbiturates Block Sodium and Potassium Conductance Increases in Voltage-Clamped Lobster AxonsThe Journal of general physiology, 1968
- Iontophoretic studies of neurones in the mammalian cerebral cortexThe Journal of Physiology, 1963