Abstracts

RATIONALE: Kainate receptors have been implicated in the pathogenesis of epilepsy and contribute to seizures in hippocampal area CA3. The epileptogenic effect of these receptors may result from their ability to both reduce GABAergic inhibition and directly excite principal cells. The subunit composition of kainate receptors in area CA3 varies according to cell type with pyramidal cells expressing primarily GluR6, KA1 and KA2 subunits, whereas CA3 inhibitory interneurons express primarily GluR5 and KA2 subunits. We have previously found that GluR6 kainate receptors are regulated by a host of physiological modulators, including protons, polyamines, redox agents and zinc. In this study we have examined whether the sensitivity of kainate receptors to these modulators is affected by the subunit composition of the receptor. METHODS: Two electrode voltage clamp was used to record currents from recombinant receptors expressed in Xenopus oocytes. RESULTS: We have found that heteromeric GluR6/KA2 kainate receptors are more sensitive to modulation by each of these agents than are homomeric GluR6 receptors. The polyamine spermine (1 mM) potentiated GluR6R receptors by 30 8%, but GluR6R/KA2 receptors by 76 12% (n = 8, p < 0.01). Similarly GluR6R/KA2 receptors were more strongly inhibited by protons than were homomeric receptors. Redox agents also had a subunit dependent effect on kainate receptors. GluR6Q receptors were potentiated by 35 5% following treatment with the sulfhydryl reducing agent dithiothreitol, whereas GluR6Q/KA2 receptors were potentiated by 80 14%, a significant increase (n = 5, p < 0.05). Finally, GluR6R receptors were inhibited by zinc with an IC50 of 67 8 M, whereas heteromeric GluR6R/KA2 receptors were 18 fold more sensitive (IC50 = 3.8 2 M, n = 8). The editing state of the Q/R site on the GluR6 subunit did not alter sensitivity to any of these modulators. CONCLUSIONS: These findings suggest that the sensitivity of kainate receptors to modulation depends upon their subunit composition and that the KA2 subunit enhances this sensitivity. Supported by the Epilepsy Foundation (DM), the University Research Committee of Emory University (DM) and the NIH (RD).