Steroid Modulation Of Nonnmda Receptors

The non-NMDA glutamate receptors may be subdivided into kainate and AMPA-preferring receptors, although in practice, kainate is typically used in physiological studies of AMPA receptors in spite of its lower potency than AMPA, because of its greater efficacy and slower desensitization of AMPA receptors. Molecular cloning has revealed that the AMPA receptors may be assembled from GluR1-4 subunits (18,74-76), whereas expression of GluR5-7 yields kainate receptors. Although a clear delineation of their respective functions in vivo has been difficult to elucidate owing to their overlapping agonist sensitivities and the lack of highly selective antagonists, AMPA receptors are thought to play important roles in synaptic plasticity (77) and nervous system development (78). AMPA receptors have been found clustered at postsynaptic sites (79), consistent with the idea that they serve as the primary depolarizing receptors for mediation of fast excitatory neurotransmission. Although high-affinity kainate receptors are abundantly expressed in mammalian brain (80), the role of kainate receptors in CNS synaptic transmission is unclear. In the peripheral nervous system, kainate receptors have been characterized in dorsal root ganglion neurons, and exhibit a rapidly desensitizing response to kainate (81). In the CNS, kainate receptors have been postulated to be either located presynaptically (82,83) or localized to dendrites (84,85). At presynaptic sites, a modulatory role in which kainate receptors regulate neurotransmitter release has been proposed (86).

Fig. 3. Modulation of recombinant glutamate receptors by neuroactive steroids. A summary chart is shown that illustrates the effects of selected neuroactive steroids on recombinant NMDA, AMPA, and kainate receptors expressed in Xenopus oocytes. Oocytes were injected with cRNA encoding heteromeric NR1 :NR2A NMDA, homomeric GluR3 (flop) AMPA, or homomeric GluR6 kainate receptor subunits. Following 3-5 d of incubation, two-electrode voltage clamp recording was used to measure steroid modulation of responses to 100 \x.M NMDA, 100 ^M kainate, and 10 ^M kainate responses, respectively, for the three glutamate receptor subtypes. Bars indicate the percentage change in the agonist induced current in the presence of the indicated steroid, as compared to the current in the absence of steroid. Steroids were applied at a concentration of 100 ^M and oocytes were pre-equilibrated with steroid for 10 s prior to coapplication of steroid and agonist with all solutions containing 5% DMSO. VH = -100 mV.

Fig. 3. Modulation of recombinant glutamate receptors by neuroactive steroids. A summary chart is shown that illustrates the effects of selected neuroactive steroids on recombinant NMDA, AMPA, and kainate receptors expressed in Xenopus oocytes. Oocytes were injected with cRNA encoding heteromeric NR1 :NR2A NMDA, homomeric GluR3 (flop) AMPA, or homomeric GluR6 kainate receptor subunits. Following 3-5 d of incubation, two-electrode voltage clamp recording was used to measure steroid modulation of responses to 100 \x.M NMDA, 100 ^M kainate, and 10 ^M kainate responses, respectively, for the three glutamate receptor subtypes. Bars indicate the percentage change in the agonist induced current in the presence of the indicated steroid, as compared to the current in the absence of steroid. Steroids were applied at a concentration of 100 ^M and oocytes were pre-equilibrated with steroid for 10 s prior to coapplication of steroid and agonist with all solutions containing 5% DMSO. VH = -100 mV.

Steroid modulation of non-NMDA receptors has been studied in less depth than NMDA receptors, but it is clear that many neuroactive steroids also affect this class of glutamate receptors. In contrast to NMDA receptors, almost all reported steroid effects on kainate and AMPA receptors have been inhibitory. In particular, PREGS, which greatly potentiates NMDA-induced currents, inhibits kainate- and AMPA-induced currents (19) of chick spinal cord neurons in culture. Similar results are obtained with recombinant kainate and AMPA receptors expressed in Xenopus oocytes. As shown in Fig. 3, PREGS potentiates the NMDA-induced current in oocytes expressing NR110o and NR2A subunits of the NMDA receptor, but inhibits kainate-induced currents in oocytes expressing GluR3 AMPA receptor or GluR6 kainate receptor subunits. On the other hand, DHEAS and 17 P-estradiol-3-sulfate show little, if any, activity on all three glutamate receptor subtypes, whereas pregnanolone sulfate, which is inhibitory for NMDA receptors, is also inhibitory for kainate and AMPA receptors (73,87). In view of evidence that steroid positive and negative modulatory sites of the NMDA receptor are distinct, it is tempting to speculate that a negative modulatory site might be conserved in all glutamate gated ion channels, but that the positive modulatory site might be unique to NMDA receptors. On the other hand, electrophysiological studies on hippocampal slices from ovariectomized rats reported increases in excitatory postsynaptic potential (EPSP) amplitude and potentiation of AMPA and kainate responses by 10 nM estradiol (88)—a rather surprising finding, because modulatory effects of steroids on glutamate receptors have generally been found to occur in the micromolar concentration range. The same group, however, later reported no effect of either 100 nM estradiol or 100 ^M PREGS on kainate-induced currents in outside-out patch recordings from hippocampal CA1 neurons (25). A potentiating effect of 17^-estradiol on some types of non-NMDA receptors could possibly account for the apparently paradoxical findings that 17^-estradiol inhibits NMDA responses of rat hippocampal neurons in culture (61), but acutely potentiates glutamate responses of rat cerebellar Purkinje cells (22,89).

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