Technical Reference #97

97.

Steroid Potentiation And Inhibition Of N-Methyl-D-Aspartate Receptor-Mediated Intracellular Ca++ Responses: Structure-Activity Studies Irwin; R.P.; Lin; S.Z.; Rogawski; M.A.; Purdy; R.H.; and Paul; S.M., National Institute of Mental Health, Pharmacology and Experimental Therapeutics, 271(97), (1994)
Link To Paper

Abstract:
Pregnenolone sulfate and 15 related steroids were investigated for their effects on N-methyl-D-aspartate (NMDA)-induced elevations in intracellular Ca++ ([Ca++]i) in cultured rat hippocampal neurons by microspectrofluorimetry with the Ca(++)-sensitive indicator fura-2. Several pregn-5-ene steroids markedly potentiated NMDA-mediated [Ca++]i responses. Pregnenolone sulfate and its 21-acetoxy derivative and pregnenolone hemisuccinate were the most active. At a concentration of 50 microM each produced approximately 300% potentiation of 5 microM NMDA responses. In addition several steroids were identified that inhibited NMDA-induced elevations in [Ca++]i the most potent of which was 3 alpha-hydroxy-5 beta-pregnan-20-one sulfate (IC50 37 microM). Concentration-response curves for NMDA in the presence of active steroids revealed noncompetitive interaction(s) of these steroids with the NMDA receptor. Although the mechanism(s) responsible for either steroid-induced augmentation or inhibition of NMDA-receptor responses is unknown these data suggest the presence of one or more steroid recognition sites with a high degree of structural specificity associated with NMDA receptors. These results further raise the possibility that pregn-5-ene 3-sulfates and pregnane 3-sulfates could be endogenous modulators of NMDA receptor-mediated synaptic events.

Cell Type(s)
Neurons - Hippocampal