Send to

Choose Destination
See comment in PubMed Commons below
Mol Pharmacol. 1994 Jul;46(1):146-50.

3 alpha-Hydroxy-5 beta-pregnan-20-one sulfate: a negative modulator of the NMDA-induced current in cultured neurons.

Author information

Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Massachusetts 02118.


We have shown previously that the neurosteroid pregnenolone sulfate acts as a positive allosteric modulator at the N-methyl-D-aspartate (NMDA) receptor while inhibiting the kainate, the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), the glycine, and the gamma-aminobutyric acid (GABA) responses of chick spinal cord neurons. Here, we report that 3 alpha-hydroxy-5 beta-pregnan-20-one sulfate (5 beta 3 alpha S), a sulfated form of naturally occurring 5 beta 3 alpha, inhibits both the NMDA and the non-NMDA receptor-mediated responses as measured by whole cell voltage clamp recordings. 100 microM 5 beta 3 alpha S rapidly and reversibly inhibits the response to 30 microM NMDA by 66%, 50 microM kainate by 37%, and 25 microM AMPA by 29%. Application of 50 microM nonsulfated 5 beta 3 alpha does not produce any significant effect on the NMDA response, demonstrating that the sulfate moiety is important for the effect of 5 beta 3 alpha S on the NMDA response. The effect of 5 beta 3 alpha S on the NMDA response is concentration dependent, with an EC50 of 62 microM. 5 beta 3 alpha S reduces the maximum NMDA response with little effect on the NMDA EC50, indicating that antagonism of the NMDA response by 5 beta 3 alpha S is noncompetitive. The fact that 5 beta 3 alpha S inhibition of the NMDA response is neither agonist nor voltage dependent demonstrates that 5 beta 3 alpha S does not act as an open channel blocker. Furthermore, inhibition of the NMDA response by 5 beta 3 alpha S is not reduced by the addition of a maximal concentration (10 microM) of glycine, indicating that 5 beta 3 alpha S does not act via the glycine recognition site. The inhibitory action of 5 beta 3 alpha S on the NMDA and non-NMDA receptors may provide a basis for inhibiting glutamate receptor-induced seizures and excitotoxic cell death.

[Indexed for MEDLINE]
PubMed Commons home

PubMed Commons

How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire
    Loading ...
    Support Center