Increased gamma-aminobutyric acid receptor function in the cerebral cortex of myoclonic calves with an hereditary deficit in glycine/strychnine receptors.
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 gamma-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 [3H]muscimol were found (KD = 9.3 +/- 1.5 and 227 +/- 41 nM, respectively), whereas only the high-affinity site was detectable in controls (KD = 14.0 +/- 3.1 nM). The density and affinity of benzodiazepine agonist binding sites labelled by [3H]diazepam were unchanged, but there was an increase in GABA-stimulated benzodiazepine binding. The affinity for t-[3H]butylbicyclo-o-benzoate, a ligand that binds to the GABA-activated chloride channel, was significantly increased in ICM brain membranes (KD = 148 +/- 14 nM) compared with controls (KD = 245 +/- 33 nM). Muscimol-stimulated 36Cl- 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Lummis
S C
SC
Department of Pharmacology, University of Sydney, New South Wales, Australia.
Gundlach
A L
AL
Johnston
G A
GA
Harper
P A
PA
Dodd
P R
PR
D000818:Animals; D001569:Benzodiazepines / Q000378:metabolism; D001643:Bridged Bicyclo Compounds / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002417:Cattle; D002540:Cerebral Cortex / Q000378:metabolism*; D018118:Chloride Channels; D002712:Chlorides / Q000378:metabolism; D002713:Chlorine; D003975:Diazepam / Q000378:metabolism; D005260:Female; D008024:Ligands; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D009118:Muscimol / Q000378:metabolism / Q000494:pharmacology; D009207:Myoclonus / Q000235:genetics / Q000378:metabolism*; D011868:Radioisotopes; D011963:Receptors, GABA-A / Q000378:metabolism*; D018009:Receptors, Glycine; D017981:Receptors, Neurotransmitter / Q000172:deficiency*; D013570:Synaptic Membranes / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018118:Chloride Channels; D002712:Chlorides; D008024:Ligands; D008565:Membrane Proteins; D011868:Radioisotopes; D011963:Receptors, GABA-A; D018009:Receptors, Glycine; D017981:Receptors, Neurotransmitter; C027822:strychnine receptor; D001569:Benzodiazepines; D009118:Muscimol; D002713:Chlorine; D005680:gamma-Aminobutyric Acid; C046308:tert-butylbicyclo-2-benzoate; D003975:Diazepam