Department of Pharmacology (M.A.J., A.J., S.F.T.) and Department of Anesthesiology (A.J.), School of Medicine, and Department of Chemistry (G.W., J.P.S.), Emory University, Atlanta, Georgia; Department of Neuroscience and Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland (J.B., R.L.H.); and Department of Molecular Medicine, Cornell University, Ithaca, New York (R.E.O.).
Mol Pharmacol. 2014 Apr;85(4):618-29. doi: 10.1124/mol.113.091488. Epub 2014 Jan 22.
Three residues within the AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor subunit GluA1 C terminus (Ser818, Ser831, Thr840) can be phosphorylated by Ca(2+)/phospholipid-dependent protein kinase (PKC). Here, we show that PKC phosphorylation of GluA1 Ser818 or Thr840 enhances the weighted mean channel conductance without altering the response time course or agonist potency. These data support the idea that these residues constitute a hyper-regulatory domain for the AMPA receptor. Introduction of phosphomimetic mutations increases conductance only at these three sites within the proximal C terminus, consistent with a structural model with a flexible linker connecting the distal C-terminal domain to the more proximal domain containing a helix bracketed by Ser831 and Thr840. NMR spectra support this model and raise the possibility that phosphorylation can alter the configuration of this domain. Our findings provide insight into the structure and function of the C-terminal domain of GluA1, which controls AMPA receptor function and trafficking during synaptic plasticity in the central nervous system.
谷氨酸 AMPA 受体亚基 GluA1 C 端的三个残基（Ser818、Ser831、Thr840）可被 Ca2+/磷脂依赖性蛋白激酶（PKC）磷酸化。在这里，我们发现 PKC 对 GluA1 Ser818 或 Thr840 的磷酸化增强了加权平均通道电导，而不改变反应时程或激动剂效力。这些数据支持这些残基构成 AMPA 受体的超调节域的观点。在近 C 端，引入磷酸模拟突变只会增加电导，这与一个结构模型一致，该模型具有一个连接远端 C 末端结构域和更靠近的包含 Ser831 和 Thr840 之间的螺旋的灵活连接子。NMR 谱支持该模型，并提出磷酸化可能改变该结构域的构象的可能性。我们的发现为 GluA1 的 C 端结构域的结构和功能提供了深入了解，该结构域控制着中枢神经系统中突触可塑性期间 AMPA 受体的功能和运输。
