Abstracts

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. We have previously shown that synaptic kainate receptors are inhibited by physiologically released zinc in hippocampal mossy fiber synapses. In addition, using recombinant kainate receptors we have found that zinc inhibition of these receptors is subunit dependent. We have also found that kainate receptors are inhibited by protons. Proton concentrations increase markedly during seizures with pH levels falling to 6.5 or below. To better understand the impact of seizures on kainate receptor-mediated neurotransmission, we have now examined the effect of protons on zinc inhibition of kainate receptors.
Two electrode voltage clamp was used to record currents from recombinant receptors expressed in [italic]Xenopus[/italic] oocytes.
Protons shifted the zinc dose response curve to the right, indicating that when proton concentrations increased a given concentration of zinc produced less inhibition. The effect of protons on zinc inhibition of kainate receptors was subunit dependent. Lowering pH from 7.5 to 6.0 had a substantially greater effect on the IC[sub]50 [/sub]for zinc inhibition of GluR6R/KA2 receptors (150 fold increase) than on homomeric GluR6R receptors (6 fold increase). Examination of the proton inhibition curve for GluR6/KA2 receptors revealed that in the presence of zinc protons potentiated the current over a physiological range of pH values with greater potentiation at more acidic pH levels. Proton potentiation was greater as the concentration of zinc was increased from 1 to 1000 uM, indicating that the potentiation reflects relief of zinc inhibition.
These findings indicate an interaction between proton and zinc inhibition of kainate receptors. During repetitive synaptic activity, such as seizures, released zinc inhibits kainate receptors. Acidification of the synaptic cleft during the seizure would relieve this inhibition, thereby increasing kainate neurotransmission. Thus, a major effect of a transient fall in pH during a seizure could be an unmasking of kainate receptor-mediated synaptic transmission.
[Supported by: NINDS (DM, RD) and NARSAD (DM).]