Micromolar-affinity benzodiazepine receptors regulate voltage-sensitive calcium channels in nerve terminal preparations.
Benzodiazepines in micromolar concentrations significantly inhibit depolarization-sensitive Ca2+ uptake in intact nerve-terminal preparations. Benzodiazepine inhibition of Ca2+ uptake is concentration dependent and stereospecific. Micromolar-affinity benzodiazepine receptors have been identified and characterized in brain membrane and shown to be distinct from nanomolar-affinity benzodiazepine receptors. Evidence is presented that micromolar, and not nanomolar, benzodiazepine binding sites mediate benzodiazepine inhibition of Ca2+ uptake. Irreversible binding to micromolar benzodiazepine binding sites also irreversibly blocked depolarization-dependent Ca2+ uptake in synaptosomes, indicating that these compounds may represent a useful marker for identifying the molecular components of Ca2+ channels in brain. Characterization of benzodiazepine inhibition of Ca2+ uptake demonstrates that these drugs function as Ca2+ channel antagonists, because benzodiazepines effectively blocked voltage-sensitive Ca2+ uptake inhibited by Mn2+, Co2+, verapamil, nitrendipine, and nimodipine. These results indicate that micromolar benzodiazepine binding sites regulate voltage-sensitive Ca2+ channels in brain membrane and suggest that some of the neuronal stabilizing effects of micromolar benzodiazepine receptors may be mediated by the regulation of Ca2+ conductance.
D000818:Animals; D001569:Benzodiazepines / Q000378:metabolism*; D001921:Brain / Q000502:physiology*; D002118:Calcium / Q000378:metabolism*; D002413:Cations, Divalent; D002998:Clonazepam / Q000378:metabolism; D003975:Diazepam / Q000378:metabolism; D005260:Female; D005445:Flunitrazepam / Q000378:metabolism; D007473:Ion Channels / Q000502:physiology*; D007700:Kinetics; D051381:Rats; D011919:Rats, Inbred Strains; D011956:Receptors, Cell Surface / Q000502:physiology*; D011963:Receptors, GABA-A; D013574:Synaptosomes / Q000502:physiology*
D002413:Cations, Divalent; D007473:Ion Channels; D011956:Receptors, Cell Surface; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D002998:Clonazepam; D005445:Flunitrazepam; D003975:Diazepam; D002118:Calcium