Molecular Mechanism of Pregnenolone Sulfate Action at NR1/NR2B Receptors

Abstract

These results suggest that the PS is a modulator of NMDA receptor P o , the effectiveness of which is lowered by glutamate binding. This modulation may have important consequences for the neuronal excitability.

Neurosteroid regulation of central nervous system development

“…Pregnenolone sulfate acts at many different ligand-gated ionchannel receptors. It is a negative modulator of GABA A receptors (Majewska et al, 1985;Majewska and Schwartz, 1987;Rabow et al, 1995), kainate and AMPA receptors (Mameli et al, 2005;Shirakawa et al, 2005;Spivak et al, 2004;Wu and Chen, 1997), and it is a positive modulator of NMDA receptors (Bowlby, 1993;Horak et al, 2004;Irwin et al, 1994;ParkChung et al, 1997;Wu et al, 1991). Hence, pregnenolone and pregnenolone sulfate are excitatory neurosteroids.…”

20-Oxo-5β-Pregnan-3α-yl Sulfate Is a Use-Dependent NMDA Receptor Inhibitor

“…We have shown recently that PS, a neurosteroid structurally similar to 3␣5␤S, has a positive and negative effect on NMDA receptors and further that the structure of the extracellular M3-M4 loop of the NR2 subunit is critical for the expression of both effects (Malayev et al, 2002;Horak et al, 2004Horak et al, , 2005. To explore the molecular basis of 3␣5␤S action at NR2 subunits, which may be similar to the inhibitory effect of PS, we used a chimera (NR2A3C4A) in which the extracellular M3-M4 loop of the NR2A subunit, which is less sensitive to the inhibitory effect of 3␣5␤S, was exchanged for the homologous region of the NR2C subunit, which is more sensitive to the inhibitory effect of 3␣5␤S.…”

“…We have shown previously that PS is a disuse-dependent NMDA receptor modulator with action that depends on the relative timing of the application of agonist and neurosteroid (Malayev et al, 2002;Horak et al, 2004). To test whether 3␣5␤S has an action similar to PS at NMDA receptors, two protocols of 3␣5␤S and glutamate applications were used: (1) a coapplication of 3␣5␤S and glutamate made after the onset of the response to glutamate and (2) a sequential application of glutamate after preapplication of 3␣5␤S for 37 s. Figure 2 A1 shows responses of NR1-1a/NR2B receptors to a coapplication of 3␣5␤S (300 M) with glutamate made after the onset of the response.…”

“…They are both synthesized de novo in the CNS and modified to neuroactive compounds from circulating precursors and can reach a high local concentration (Mellon and Griffin, 2002;Kawato et al, 2003). It has been well established that neurosteroids exert a positive, negative, or combined effect on NMDA receptors (Wu et al, 1991;Bowlby, 1993;Park-Chung et al, 1994;Horak et al, 2004). Pregnenolone sulfate (PS), an endogenously occurring neurosteroid, acts in a subunit-dependent manner as a combined positive and negative modulator of NMDA receptors (Malayev et al, 2002;Horak et al, 2004).…”

“…It has been well established that neurosteroids exert a positive, negative, or combined effect on NMDA receptors (Wu et al, 1991;Bowlby, 1993;Park-Chung et al, 1994;Horak et al, 2004). Pregnenolone sulfate (PS), an endogenously occurring neurosteroid, acts in a subunit-dependent manner as a combined positive and negative modulator of NMDA receptors (Malayev et al, 2002;Horak et al, 2004). The mechanism of action of PS associated with a positive effect is disuse dependent (i.e., NMDA receptor affinity for PS is decreased during receptor activation) and involves an increase in the peak probability of the NMDA receptor opening (P o ).…”