Auxiliary Subunit GSG1L Acts to Suppress Calcium-Permeable AMPA Receptor Function
Auxiliary Subunit GSG1L Acts to Suppress Calcium-Permeable AMPA Receptor Function
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DOI：
10.1523/jneurosci.2152-15.2015
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发表时间：
2015-12-09
影响因子：
5.3
通讯作者：
Cull-Candy, Stuart G.
中科院分区：
文献类型：
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作者：
McGee, Thomas P.;Bats, Cecile;Cull-Candy, Stuart G.
AMPA型谷氨酸受体是配体门控阳离子通道，负责大脑中大部分快速兴奋性突触传递。它们的行为和钙渗透性关键取决于它们的亚基组成和相关辅助蛋白的身份。钙渗透性AMPA受体（CP-AMPAR）有助于各种形式的突触可塑性，它们的功能障碍是许多严重神经系统疾病的基础。对于CP-AMPAR，作为辅助亚基的原型跨膜AMPAR调节蛋白stargazin通过增加单通道电导、减慢通道门控、增加钙渗透性和缓解内源性细胞内多胺的电压依赖性阻断来增强受体功能。我们发现，相比之下，GSG 1 L，跨膜辅助蛋白最近确定为AMPAR蛋白质组的一部分，作用于减少加权平均单通道电导和钙渗透性的重组CP-AMPAR，同时增加多胺依赖整流。为了研究GSG 1 L对天然AMPAR的影响，我们操纵了其在小脑和海马神经元中的表达。将GSG 1 L转染到缺乏这种蛋白的小鼠培养的小脑星状细胞中，增加了mEPSC的内向整流。相反，在大鼠培养的海马锥体神经元中，shRNA介导的内源性GSG 1 L敲低导致mEPSC振幅和潜在的加权平均单通道电导增加，这表明GSG 1 L的作用是抑制通过天然CP-AMPAR的电流。因此，我们的数据表明，GSG 1 L扩展了AMPAR辅助亚基的功能库，这不仅可以增强，而且可以减少通过其相关的AMPAR的电流。
AMPA-type glutamate receptors are ligand-gated cation channels responsible for a majority of the fast excitatory synaptic transmission in the brain. Their behavior and calcium permeability depends critically on their subunit composition and the identity of associated auxiliary proteins. Calcium-permeable AMPA receptors (CP-AMPARs) contribute to various forms of synaptic plasticity, and their dysfunction underlies a number of serious neurological conditions. For CP-AMPARs, the prototypical transmembrane AMPAR regulatory protein stargazin, which acts as an auxiliary subunit, enhances receptor function by increasing single-channel conductance, slowing channel gating, increasing calcium permeability, and relieving the voltage-dependent block by endogenous intracellular polyamines. We find that, in contrast, GSG1L, a transmembrane auxiliary protein identified recently as being part of the AMPAR proteome, acts to reduce the weighted mean single-channel conductance and calcium permeability of recombinant CP-AMPARs, while increasing polyamine-dependent rectification. To examine the effects of GSG1L on native AMPARs, we manipulated its expression in cerebellar and hippocampal neurons. Transfection of GSG1L into mouse cultured cerebellar stellate cells that lack this protein increased the inward rectification of mEPSCs. Conversely, shRNA-mediated knockdown of endogenous GSG1L in rat cultured hippocampal pyramidal neurons led to an increase in mEPSC amplitude and in the underlying weighted mean single-channel conductance, revealing that GSG1L acts to suppress current flow through native CP-AMPARs. Thus, our data suggest that GSG1L extends the functional repertoire of AMPAR auxiliary subunits, which can act not only to enhance but also diminish current flow through their associated AMPARs.