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Increased γ‐Aminobutyric Acid Receptor Function in the Cerebral Cortex of Myoclonic Calves with an Hereditary Deficit in Glycine/Strychnine Receptors
Author(s) -
Lummis Sarah C. R.,
Gundlach Andrew L.,
Johnston Graham A. R.,
Harper Peter A. W.,
Dodd Peter R.
Publication year - 1990
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.1990.tb04153.x
Subject(s) - muscimol , strychnine , glycine receptor , picrotoxin , gabaa receptor , endocrinology , medicine , cerebral cortex , receptor , glycine , agonist , chemistry , aminobutyric acid , biology , biochemistry , amino acid
Inherited congenital myoclonus (ICM) of Poll Hereford cattle is a neurological disease in which there are severe alterations in spinal cord glycine‐mediated neurotransmission. There is a specific and marked decrease, or defect, in glycine receptors and a significant increase in neuronal (synaptosomal) glycine uptake. Here we have examined the characteristics of the cerebral γ‐aminobutyric acid (GABA) receptor complex, and demonstrate that the malfunction of the spinal cord inhibitory system is accompanied by a change in the major inhibitory system in the cerebral cortex. In synaptic membrane preparations from ICM calves, both high‐ and low‐affinity binding sites for the GABA agonist [ 3 H]muscimol were found ( K D = 9.3 ± 1.5 and 227 ± 41 n M , respectively), whereas only the high‐affinity site was detectable in controls ( K D = 14.0 ± 3.1 n M ). The density and affinity of benzodiazepine agonist binding sites labelled by [ 3 H]diazepam were unchanged, but there was an increase in GABA‐stimulated benzodiazepine binding. The affinity for t ‐[ 3 H]butylbicyclo‐ o ‐benzoate, a ligand that binds to the GABA‐activated chloride channel, was significantly increased in ICM brain membranes ( K D = 148 ± 14 n M ) compared with controls ( K D = 245 ± 33 n M ). Muscimol‐stimulated 36 Cl ‐ uptake was 12% greater in microsacs prepared from ICM calf cerebral cortex, and the uptake was more sensitive to block by the GABA antagonist picrotoxin. The results show that the characteristics of the GABA receptor complex in ICM calf cortex differ from those in cortex from unaffected calves, a difference that is particularly apparent for the low‐affinity, physiologically relevant GABA receptors. Study of the GABA receptor complex in ICM calves may provide a greater insight into the interactions of the various binding sites on the GABA‐benzodiazepine receptor protein molecule.