Contributions of different kainate receptor subunits to the properties of recombinant homomeric and heteromeric receptors.
Contributions of different kainate receptor subunits to the properties of recombinant homomeric and heteromeric receptors.
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DOI：
10.1016/j.neuroscience.2014.08.009
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发表时间：
2014-10-10
期刊：
影响因子：
3.3
通讯作者：
Fisher, J. L.
中科院分区：
文献类型：
--
作者：
Fisher, M. T.;Fisher, J. L.
四聚体红藻氨酸受体可以由五种不同亚基亚型的组合组装而成。虽然GluK 1 -3亚基可以形成同源受体，但GluK 4和GluK 5需要异聚体伴侣来组装，运输到膜表面，并产生功能通道。先前的研究表明，GluK 4或GluK 5亚基的掺入改变了受体药理学和通道动力学。我们直接比较了含有GluK 4或GluK 5与GluK 1或GluK 2亚基组合的重组受体的功能特征。此外，我们利用GluK 1，GluK 2或GluK 5激动剂结合位点内的突变来分离异聚体受体内野生型伴侣的反应。我们的研究结果表明，GluK 1和GluK 2主要在其药理学性质不同，但GluK 4和GluK 5具有不同的功能特性。特别是，虽然激动剂仅与GluK 5亚基结合似乎将通道激活至非脱敏状态，但与GluK 4结合确实产生一些脱敏。这表明GluK 4和GluK 5在对受体脱敏的贡献方面存在根本差异。此外，GluK 5的激动剂结合位点的突变导致具有类似于同聚GluK 1或GluK 2受体的谷氨酸敏感性的异聚受体，但其需要更高的激动剂浓度来产生脱敏。这表明异聚体受体中脱敏的开始更多地由与激动剂结合的亚基的数量而不是由这些亚基的身份决定。异聚体受体对谷氨酸或红藻氨酸的反应中观察到的不同的浓度依赖性特性与其中任一亚基都可以激活通道的模型一致，但是需要二聚体内两个亚基的占用以允许GluK 2/K5受体的脱敏。
The tetrameric kainate receptors can be assembled from a combination of five different subunit subtypes. While GluK1-3 subunits can form homomeric receptors, GluK4 and GluK5 require a heteromeric partner to assemble, traffic to the membrane surface, and produce a functional channel. Previous studies have shown that incorporation of a GluK4 or GluK5 subunit changes both receptor pharmacology and channel kinetics. We directly compared the functional characteristics of recombinant receptors containing either GluK4 or GluK5 in combination with the GluK1 or GluK2 subunit. In addition, we took advantage of mutations within the agonist binding sites of GluK1, GluK2, or GluK5 to isolate the response of the wild-type partner within the heteromeric receptor. Our results suggest that GluK1 and GluK2 differ primarily in their pharmacological properties, but that GluK4 and GluK5 have distinct functional characteristics. In particular, while binding of agonist to only the GluK5 subunit appears to activate the channel to a non-desensitizing state, binding to GluK4 does produce some desensitization. This suggests that GluK4 and GluK5 differ fundamentally in their contribution to receptor desensitization. In addition, mutation of the agonist binding site of GluK5 results in a heteromeric receptor with a glutamate sensitivity similar to homomeric GluK1 or GluK2 receptors, but which requires higher agonist concentrations to produce desensitization. This suggests that onset of desensitization in heteromeric receptors is determined more by the number of subunits bound to agonist than by the identity of those subunits. The distinct, concentration-dependent properties observed with heteromeric receptors in response to glutamate or kainate are consistent with a model in which either subunit can activate the channel, but in which occupancy of both subunits within a dimer is needed to allow desensitization of GluK2/K5 receptors.
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