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Modulation of homomeric and heteromeric kainate receptors by the auxiliary subunit Neto1

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The Journal of Physiology

Published online on

Abstract

Abstract  The ionotropic glutamate receptors are primary mediators of fast excitatory neurotransmission, and their properties are determined both by their subunit composition and their association with auxiliary subunits. The Neto1 and Neto2 proteins have been recently identified as auxiliary subunits for kainate‐type glutamate receptors. Heteromeric kainate receptors can be assembled from varying combinations of low affinity (GluK1–3) and high‐affinity (GluK4–5) subunits. To better understand the functional impact of auxiliary subunits on kainate receptors, we examined the effect of Neto1 on the responses of recombinant homomeric and heteromeric kainate receptors to varying concentrations of glutamate. We found that co‐expression of Neto1 with homomeric GluK2 receptors had a small effect on sensitivity of the receptors to glutamate, but decreased the onset of desensitization while speeding recovery from desensitization. In the absence of Neto1, addition of GluK5 subunits to form GluK2/K5 heteromeric receptors slowed the onset of desensitization at low glutamate concentrations, compared to GluK2 homomers. Co‐expression of Neto1 with GluK2/5 receptors further enhanced these effects, essentially eliminating desensitization at μM glutamate concentrations without altering the EC50 for activation by glutamate. In addition, a prominent rebound current was observed upon removal of the agonist. The rate of recovery from desensitization was increased to the same degree by Neto1 for both homomeric GluK2 and heteromeric GluK2/K5 receptors. Expression of Neto1 with GluK1/K5, GluK3/K5 or GluK2/K4 receptors produced qualitatively similar effects on whole‐cell currents, suggesting that the impact of Neto1 on the desensitization properties of heteromeric receptors was not subunit dependent. These results provide greater insight into the functional effects of the auxiliary subunit Neto1 on both homomeric and heteromeric kainate receptors. Alteration of the characteristics of desensitization at both sub‐maximal and saturating glutamate concentrations could influence the responsiveness of these receptors to repeated stimuli. As a result, assembly of kainate receptors with the Neto auxiliary subunits could change the kinetic properties of the neuronal response to glutamatergic input. This article is protected by copyright. All rights reserved.