Lu Wei, Khatri Latika, Ziff Edward B
From the Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016.
From the Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016
J Biol Chem. 2014 Jul 4;289(27):19218-30. doi: 10.1074/jbc.M113.511246. Epub 2014 May 15.
The GluA2 subunit of the AMPA receptor (AMPAR) dominantly blocks AMPAR Ca(2+) permeability, and its trafficking to the synapse regulates AMPAR-dependent synapse Ca(2+) permeability. Here we show that GluA2 trafficking from the endoplasmic reticulum (ER) to the plasma membrane of cultured hippocampal neurons requires Ca(2+) release from internal stores, the activity of Ca(2+)/calmodulin activated kinase II (CaMKII), and GluA2 interaction with the PDZ protein, PICK1. We show that upon Ca(2+) release from the ER via the IP3 and ryanodine receptors, CaMKII that is activated enters a complex that contains PICK1, dependent upon the PICK1 BAR (Bin-amphiphysin-Rvs) domain, and that interacts with the GluA2 C-terminal domain and stimulates GluA2 ER exit and surface trafficking. This study reveals a novel mechanism of regulation of trafficking of GluA2-containing receptors to the surface under the control of intracellular Ca(2+) dynamics and CaMKII activity.
AMPA受体（AMPAR）的GluA2亚基主要阻断AMPAR的Ca(2+)通透性，其向突触的转运调节着依赖AMPAR的突触Ca(2+)通透性。在此，我们表明，培养的海马神经元中，GluA2从内质网（ER）转运至质膜需要从内部储存库释放Ca(2+)、Ca(2+)/钙调蛋白激活激酶II（CaMKII）的活性以及GluA2与PDZ蛋白PICK1的相互作用。我们发现，当通过IP3和雷诺丁受体从内质网释放Ca(2+)时，被激活的CaMKII进入一个包含PICK1的复合物，该复合物依赖于PICK1的BAR（Bin-双栖蛋白-Rvs）结构域，并与GluA2的C末端结构域相互作用，刺激GluA2从内质网输出并向表面转运。这项研究揭示了在细胞内Ca(2+)动态变化和CaMKII活性控制下，含GluA2受体向表面转运的一种新的调节机制。
