Age-related changes of GABA-activated chloride channel properties in brain cortex synaptic plasma membrane: evidence for phospholipase involvement.
Brain aging decreases binding of tert-butylbicyclophosphorothionate (TBPS), a specific ligand for Cl- channels, but has no effect on Cl- influx. Detailed studies on the kinetics of TBPS dissociation allowed the characterization of Cl- channel properties. Aging lowers, exclusively in the presence of GABA agonist, muscimol, the half-life of the fast phase of TBPS dissociation, indicating an opening time of receptor-dependent Cl- channels shorter than that in adult brain. The half-life of the slow phase of TBPS dissociation is significantly lower in aged brain in the presence and absence of muscimol. These results suggest a sustained Cl- current, including also the other channel(s) not connected with GABAA receptor activation. The analysis of biphasic TBPS dissociation demonstrates a lowered number of binding sites resulted in the reduction of the number of Cl- channels in the "open" state. This may explain an observed decrease of TBPS binding in aged brain. One of the possible factors involved in modification of GABAA receptor behavior during aging may be arachidonic acid or diacylglycerol, known to be accumulated in aged brain. The action of these compounds on the Cl- channel, observed in this study, correlates well with the effect of aging.
Samochocki
M
M
Laboratory of Cellular Signalling, Medical Research Center, Polish Academy of Sciences, Warsaw.
Strosznajder
J
J
D000375:Aging / Q000378:metabolism*; D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology; D001643:Bridged Bicyclo Compounds / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002540:Cerebral Cortex / Q000254:growth & development / Q000378:metabolism*; D018118:Chloride Channels / Q000187:drug effects / Q000378:metabolism*; D002712:Chlorides / Q000378:metabolism; D003292:Convulsants / Q000378:metabolism; D004075:Diglycerides / Q000494:pharmacology; D007700:Kinetics; D009118:Muscimol / Q000494:pharmacology; D010740:Phospholipases / Q000378:metabolism*; D010852:Picrotoxin / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013462:Sulfur Radioisotopes; D013570:Synaptic Membranes / Q000187:drug effects / Q000378:metabolism*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
D016718:Arachidonic Acid; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018118:Chloride Channels; D002712:Chlorides; D003292:Convulsants; D004075:Diglycerides; D009118:Muscimol; D010740:Phospholipases; D010852:Picrotoxin; D013462:Sulfur Radioisotopes; D005680:gamma-Aminobutyric Acid; C037476:tert-butylbicyclophosphorothionate