Hippocampal AMPA receptor gating controlled by both TARP and cornichon proteins.
Hippocampal AMPA receptor gating controlled by both TARP and cornichon proteins.
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DOI：
10.1016/j.neuron.2010.11.026
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发表时间：
2010-12-22
期刊：
影响因子：
16.2
通讯作者：
Bredt, David S.
中科院分区：
文献类型：
--
作者：
Kato, Akihiko S.;Gill, Martin B.;Ho, Michelle T.;Yu, Hong;Tu, Yuan;Siuda, Edward R.;Wang, He;Qian, Yue-Wei;Nisenbaum, Eric S.;Tomita, Susumu;Bredt, David S.
跨膜AMPA受体调节蛋白（TARP）和cornichon蛋白（CNIH-2/3）独立调节AMPA受体的运输和门控。然而，这些亚基在AMPA受体复合物内相互作用的潜力是未知的。在这里，我们发现TARPs γ-4、γ-7和γ-8，而不是γ-2、γ-3或γ-5，导致AMPA受体在持续的谷氨酸应用后“再敏感化”。对于γ-8，所有GluA亚基组合都会发生再敏感化;然而，含有γ-8的海马神经元不显示再敏感化。在重组系统中，CNIH-2消除γ-8介导的再敏化，并修改AMPA受体药理学和门控以匹配海马神经元。在海马中，γ-8和CNIH-2在突触后密度中相关联，并且在γ-8敲除小鼠中CNIH-2蛋白水平显著降低。操纵神经元CNIH-2水平调节突触外和突触γ-8-AMPA受体的电生理特性。因此，γ-8和CNIH-2在功能上与常见的海马AMPA受体复合物相互作用，以协同调节动力学和药理学。
Transmembrane AMPA receptor regulatory proteins (TARPs) and cornichon proteins (CNIH-2/3) independently modulate AMPA receptor trafficking and gating. However, the potential for interactions of these subunits within an AMPA receptor complex is unknown. Here, we find that TARPs γ-4, γ-7 and γ-8, but not γ-2, γ-3 or γ-5, cause AMPA receptors to “resensitize” upon continued glutamate application. With γ-8, resensitization occurs with all GluA subunit combinations; however, γ-8-containing hippocampal neurons do not display resensitization. In recombinant systems, CNIH-2 abrogates γ-8-mediated resensitization and modifies AMPA receptor pharmacology and gating to match that of hippocampal neurons. In hippocampus, γ-8 and CNIH-2 associate in postsynaptic densities and CNIH-2 protein levels are markedly diminished in γ-8 knockout mice. Manipulating neuronal CNIH-2 levels modulates the electrophysiological properties of extrasynaptic and synaptic γ-8-containing AMPA receptors. Thus, γ-8 and CNIH-2 functionally interact with common hippocampal AMPA receptor complexes to modulate synergistically kinetics and pharmacology.
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