Cornichons modify channel properties of recombinant and glial AMPA receptors.
Cornichons modify channel properties of recombinant and glial AMPA receptors.
复制标题
DOI：
10.1523/jneurosci.0345-12.2012
复制
发表时间：
2012-07-18
期刊：
影响因子：
--
通讯作者：
Cull-Candy SG
中科院分区：
文献类型：
--
作者：
Coombs ID;Soto D;Zonouzi M;Renzi M;Shelley C;Farrant M;Cull-Candy SG
离子型谷氨酸受体是中枢神经系统中大多数兴奋性突触传递的基础，与跨膜蛋白相关，这些跨膜蛋白修饰它们的细胞内运输和通道门控。对于AMPA型谷氨酸受体（AMPAR），我们已经在跨膜AMPAR调节蛋白（TARP）的调控方面取得了重大进展。很少有人知道的功能影响cornichons -无关的AMPAR相互作用的蛋白质，通过蛋白质组学分析确定。在这里，我们证实，cornichon同系物2和3（CNIH-2和CNIH-3），但不是CNIH-1，减缓失活和脱敏的含GluA 2的钙不渗透（CI-）和GluA 2缺乏钙渗透（CP-）AMPAR在tsA 201细胞中表达。CNIH-2和CNIH-3还增强了CP-AMPAR的谷氨酸敏感性、单通道电导和钙渗透性，同时减少了细胞内多胺对它们的阻断。我们通过记录大鼠视神经少突胶质细胞前体细胞（OPC）（已知表达大量CP-AMPAR）来研究CNIH对天然AMPAR的潜在影响。这些神经胶质细胞表现出抗CNIH-2/3抗体的表面标记。其AMPAR介导的电流的两个特征-部分激动剂红藻氨酸盐（IKA/IGlu比率0.4）的相对功效和环噻嗪对红藻氨酸盐响应的大于五倍的增强-表明AMPAR与CNIH的关联。此外，CNIH-3在OPCs中的过表达显著减缓AMPAR脱敏。总而言之，我们的实验支持了这样的观点，即CNIHS能够改变AMPARs的关键特性，并表明它们可能在神经胶质中做到这一点。
Ionotropic glutamate receptors, which underlie a majority of excitatory synaptic transmission in the CNS, associate with transmembrane proteins that modify their intracellular trafficking and channel gating. For AMPA-type glutamate receptors (AMPARs), significant advances have been made in our understanding of their regulation by transmembrane AMPAR regulatory proteins (TARPs). Less is known about the functional influence of cornichons – unrelated AMPAR-interacting proteins, identified by proteomic analysis. Here we confirm that cornichon homologs 2 and 3 (CNIH-2 and CNIH-3), but not CNIH-1, slow the deactivation and desensitization of both GluA2-containing calcium-impermeable (CI-) and GluA2-lacking calcium-permeable (CP-) AMPARs expressed in tsA201 cells. CNIH-2 and -3 also enhanced the glutamate sensitivity, single-channel conductance and calcium permeability of CP-AMPARs, while decreasing their block by intracellular polyamines. We examined the potential effects of CNIHs on native AMPARs by recording from rat optic nerve oligodendrocyte precursor cells (OPCs), known to express a significant population of CP-AMPARs. These glial cells exhibited surface labelling with an anti-CNIH-2/3 antibody. Two features of their AMPAR-mediated currents – the relative efficacy of the partial agonist kainate (IKA/IGlu ratio 0.4), and a greater than five-fold potentiation of kainate responses by cyclothiazide – suggest AMPAR association with CNIHs. Additionally, overexpression of CNIH-3 in OPCs markedly slowed AMPAR desensitization. Together, our experiments support the view that CNIHs are capable of altering key properties of AMPARs and suggest that they may do so in glia.