J. L. Fisher: USC-School of Medicine, Department of Pharmacology, Physiology and Neuroscience, 6439 Garners Ferry Road, Columbia, SC 29209, USA.
J Physiol. 2013 Oct 1;591(19):4711-24. doi: 10.1113/jphysiol.2013.256776. Epub 2013 Jun 24.
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 neuropilin and tolloid-like 1 and 2 proteins (Neto1 and Neto2) have been recently identified as auxiliary subunits for kainate-type glutamate receptors. Heteromeric kainate receptors (KARs) can be assembled from varying combinations of low-affinity (GluK1-GluK3) and high-affinity (GluK4-GluK5) subunits. To better understand the functional impact of auxiliary subunits on KARs, we examined the effect of Neto1 on the responses of recombinant homomeric and heteromeric KARs 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/GluK5 heteromeric receptors slowed the onset of desensitization at low glutamate concentrations, compared with GluK2 homomers. Co-expression of Neto1 with GluK2/GluK5 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/GluK5 receptors. Expression of Neto1 with GluK1/GluK5, GluK3/GluK5 or GluK2/GluK4 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 KARs. 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 KARs with the Neto auxiliary subunits could change the kinetic properties of the neuronal response to glutamatergic input.
离子型谷氨酸受体是快速兴奋性神经递质传递的主要介质，其性质既由其亚基组成决定，也与其辅助亚基有关。神经纤毛蛋白和 Tolloid 样蛋白 1 和 2（Neto1 和 Neto2）最近被鉴定为 kainate 型谷氨酸受体的辅助亚基。异源 kainate 受体（KARs）可以由低亲和力（GluK1-GluK3）和高亲和力（GluK4-GluK5）亚基的不同组合组装而成。为了更好地了解辅助亚基对 KARs 的功能影响，我们研究了 Neto1 对重组同型和异型 KAR 对不同浓度谷氨酸反应的影响。我们发现，Neto1 与同型 GluK2 受体共表达对受体对谷氨酸的敏感性影响很小，但会降低脱敏的起始速度，同时加速脱敏的恢复。在没有 Neto1 的情况下，将 GluK5 亚基添加到形成 GluK2/GluK5 异型受体中，与 GluK2 同型相比，在低谷氨酸浓度下会减缓脱敏的起始速度。Neto1 与 GluK2/GluK5 受体共表达进一步增强了这些作用，基本上消除了 μm 谷氨酸浓度下的脱敏作用，而不改变谷氨酸激活的 EC50。此外，在去除激动剂时观察到明显的反弹电流。Neto1 对同型 GluK2 和异型 GluK2/GluK5 受体的脱敏恢复速度的影响程度相同。Neto1 与 GluK1/GluK5、GluK3/GluK5 或 GluK2/GluK4 受体共表达对全细胞电流产生了定性相似的影响，这表明 Neto1 对异型受体脱敏特性的影响不是亚基依赖性的。这些结果提供了对辅助亚基 Neto1 对同型和异型 KAR 功能影响的更深入了解。在亚最大和饱和谷氨酸浓度下，脱敏特性的改变可能会影响这些受体对重复刺激的反应性。因此，与 Neto 辅助亚基组装的 KAR 可能会改变神经元对谷氨酸输入的反应动力学特性。
