Evidence for a reduction of coupling between GABAA receptor agonist and ionophore binding sites by inorganic phosphate.
[35S]TBPS binding to the GABAA receptor ionophore binding site is anion dependent. Using autoradiography on rat brain sections, we show that permeabilities of anions through the receptor channel correlate with their efficiencies to promote basal [35S]TBPS binding. Phosphate made an exception as it induced more binding than expected from its permeability. Well-permeable anions (chloride, nitrate, formate) allowed [35S]TBPS binding to be effectively displaced by 1 mM GABA, whereas low-permeable anions (acetate, phosphate, propionate) markedly prevented this GABA effect, especially in the thalamus, the transition from the high to the low GABA effect being between formate and acetate. In the presence of phosphate, GABA enhanced [3H]flunitrazepam binding to benzodiazepine site of recombinant alpha1beta2gamma2 receptors with the same efficacy but lower potency as compared to the presence of chloride, whereas [35S]TBPS binding was abnormally modulated by GABA. These results suggest that inorganic phosphate affects coupling between agonist and ionophore sites in GABAA receptors.
Sinkkonen
Saku T
ST
Institute of Biomedicine, Pharmacology, University of Helsinki, P.O.Box 63, Helsinki, FI-00014, Finland.
Rabe
Holger
H
Lüddens
Hartmut
H
Korpi
Esa R
ER
D000818:Animals; D000838:Anions; D001665:Binding Sites; D002460:Cell Line; D018755:GABA Agonists / Q000378:metabolism*; D058785:GABA-A Receptor Agonists; D006801:Humans; D007476:Ionophores / Q000378:metabolism*; D008024:Ligands; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010710:Phosphates / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism; D011994:Recombinant Proteins / Q000819:agonists / Q000378:metabolism; D013788:Thalamus / Q000187:drug effects / Q000378:metabolism
D000838:Anions; D018755:GABA Agonists; D058785:GABA-A Receptor Agonists; D007476:Ionophores; D008024:Ligands; D010710:Phosphates; D011963:Receptors, GABA-A; D011994:Recombinant Proteins