Open AccessNeurosteroid modulation of ionotropic glutamate receptors and excitatory synaptic transmission
Author(s) -
Miloslav Sedlacek,
Miloslav Kořı́nek,
Miloš Petrović,
Ondřej Cais,
Eva Adamusová,
Hana Chodounská,
Ladislav Vyklický
Publication year - 2008
Publication title -
physiological research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.647
H-Index - 70
eISSN - 1802-9973
pISSN - 0862-8408
DOI - 10.33549/physiolres.931600
Subject(s) - kainate receptor , ampa receptor , ionotropic effect , nmda receptor , receptor , neuroactive steroid , long term depression , glutamate receptor , chemistry , ion channel linked receptors , metabotropic glutamate receptor , pregnenolone sulfate , pregnanolone , silent synapse , inhibitory postsynaptic potential , neurotransmission , microbiology and biotechnology , biology , gabaa receptor , biochemistry , neuroscience
Ionotropic glutamate receptors function can be affected by neurosteroids, both positively and negatively. N-methyl-D-aspartate (NMDA) receptor responses to exogenously applied glutamate are potentiated or inhibited (depending on the receptor subunit composition) by pregnenolone sulphate (PS) and inhibited by pregnanolone sulphate (3alpha5betaS). While PS effect is most pronounced when its application precedes that of glutamate, 3alpha5betaS only binds to receptors already activated. Synaptically activated NMDA receptors are inhibited by 3alpha5betaS, though to a lesser extent than those tonically activated by exogenous glutamate. PS, on the other hand, shows virtually no effect on any of the models of synaptically activated NMDA receptors. The site of neurosteroid action at the receptor molecule has not yet been identified, however, the experiments indicate that there are at least two distinct extracellularly located binding sites for PS mediating its potentiating and inhibitory effects respectively. Experiments with chimeric receptors revealed the importance of the extracellular loop connecting the third and the fourth transmembrane domain of the receptor NR2 subunit for the neurosteroid action. alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)/kainate receptors are inhibited by both PS and 3alpha5betaS. These neurosteroids also affect AMPA receptors-mediated synaptic transmission, however, in a rather indirect way, through presynaptically located targets of action.