Modulatory action of arachidonic acid on GABAA/chloride channel receptor function in adult and aged brain cortex membranes.
Effect of arachidonic acid on binding parameters of two binding sites on the GABAA receptor and on GABA activated Cl- uptake was investigated in synaptic plasma membrane and in synaptoneurosomes from brain cortex of adult (4-months old) and aged (27-months old) rats. The ligands used were [3H]muscimol, a GABA agonist and [35S]-t-butylbicyclophosphorothionate ([35S]TBPS), a convulsant that binds to the site near the chloride channel. Arachidonic acid increases significantly GABAA agonist binding and concomitantly decreases [35S]TBPS binding in a concentration dependent manner. The analysis of binding parameters in adult brain showed a significant decrease by AA of KD value for low but not for high affinity of [3H]muscimol binding. Concomitantly, AA enhances Bmax values for high affinity binding and has no effect on Bmax value for low affinity binding in synaptic plasma membrane (SPM) from adult brain. In synaptic plasma membrane from aged brain AA increases low and high affinity binding of agonist to GABAA receptor, modified significantly KD value by about 30 and 66%, respectively. On the other hand, AA significantly decreases of [35S]TBPS binding to chloride channel recognition site. Scatchard's analysis indicates that this inhibition results from a decrease of total number of binding sites. Moreover, the affinity of [35S]TBPS binding was increased (KD = 37.0 nM for AA-treated membrane, as compared to 69.3 nM KD in control membrane). GABA-dependent chloride uptake into synaptoneurosomes is also inhibited by AA in a concentration dependent manner in adult brain. In aged brain synaptoneurosomes AA has similar inhibitory effect on GABA-activated chloride uptake.(ABSTRACT TRUNCATED AT 250 WORDS)
Samochocki
M
M
Department of Neurochemistry, 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; D002462:Cell Membrane / Q000378:metabolism; D002540:Cerebral Cortex / Q000254:growth & development / Q000378:metabolism*; D018118:Chloride Channels / Q000187:drug effects / Q000378:metabolism*; D002712:Chlorides / Q000378:metabolism; D003292:Convulsants / Q000378:metabolism; D004281:Docosahexaenoic Acids / Q000494:pharmacology; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D009118:Muscimol / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism*; D013229:Stearic Acids / Q000494:pharmacology; D013570:Synaptic Membranes / Q000378:metabolism; D013574:Synaptosomes / Q000378:metabolism
D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018118:Chloride Channels; D002712:Chlorides; D003292:Convulsants; D005230:Fatty Acids, Nonesterified; D011963:Receptors, GABA-A; D013229:Stearic Acids; D004281:Docosahexaenoic Acids; D009118:Muscimol; D016718:Arachidonic Acid; C031183:stearic acid; C037476:tert-butylbicyclophosphorothionate