Distinct Sites for Inverse Modulation ofN-Methyl-d-Aspartate Receptors by Sulfated Steroids

Abstract

Steroid sulfation occurs in nervous tissue and endogenous sulfated steroids can act as positive or negative modulators of N-methyl-D-aspartate (NMDA) receptor function. In the current study, structure-activity relationships for sulfated steroids were examined in voltage-clamped chick spinal cord and rat hippocampal neurons in culture and in Xenopus laevis oocytes expressing NR1(100) and NR2A subunits. The ability of pregnenolone sulfate (a positive modulator) and epipregnanolone sulfate (a negative modulator) to compete with each another, as well as with other known classes of NMDA receptor modulators, was examined. The results show that steroid positive and negative modulators act at specific, extracellularly directed sites that are distinct from one another and from the spermine, redox, glycine, Mg2+, MK-801, and arachidonic acid sites. Sulfated steroids are effective as modulators of ongoing glutamate-mediated synaptic transmission, which is consistent with their possible role as endogenous neuromodulators in the CNS.

Neurosteroid regulation of central nervous system development

“…Hence, the nature of or requirement for a charged group at C3 is not clear. However, reduction of the charged residue at C3 results in ablation of activity (Park-Chung et al, 1997). Studies using pregnenolone, in which a hydroxyl group is at C3, have not been reported.…”

“…In addition to pregnenolone sulfate activating NMDA receptors, other pregn-5-ene steroids also potentiate NMDA responses (Irwin et al, 1994;Park-Chung et al, 1997). Reduction of the C21 ketone or C17 hydroxylation reduces activity at NMDA receptors, and removal of the C19 side chain to yield dehydroepiandrosterone sulfate reduces activity even further.…”

“…Studies using pregnenolone, in which a hydroxyl group is at C3, have not been reported. Compounds that act as positive or negative modulators of the NMDA receptor likely mediate these effects through distinct sites, since their effects are not altered by increased concentrations of one another (Park-Chung et al, 1997).…”

3α-hydroxy-5α-pregnan-20-one in the midbrain ventral tegmental area mediates social, sexual, and affective behaviors

“…Glutamate levels are increased in the midbrain of mated and receptive rodents that have elevated midbrain 3α,5α-THP compared with non-receptive rodents (Frye, 2001). Blocking P's metabolism to 3α,5α-THP reduces glutamate's excitatory effects (Park-Chung et al, 1997). Blocking NMDARs in the VTA enhances 3α,5α-THP-facilitated lordosis of rodents (DeBold et al, 2000;Frye and Petralia, 2003c).…”

Physiological Relevance of Pregnanolone Isomers and Their Polar Conjugates with Respect to the Gender, Menstrual Cycle and Pregnancy

“…Hill, Parizek, Kancheva, et al, 2010;Malayev, Gibbs, & Farb, 2002;Weaver, et al, 2000). On the other hand, the 5ǐ-PIC exert an antagonistic effect on NMDA-r (Malayev, et al, 2002;Park-Chung, et al, 1997;Weaver, et al, 2000) and promote their desensitization (Kussius, Kaur, & Popescu, 2009). Like the levels of other PIC, the levels of conjugated 3Ǐ,5ǐ-THP are also extremely elevated in pregnant women and (in contrast to slightly increasing, stagnating or even decreasing levels of GABAergic PI) pronouncedly rise in the late pregnancy (Gilbert Evans, Ross, Sellers, Purdy, & Romach, 2005; M. Hill, et al, 2007;M.…”