N-甲基-D-天冬氨酸（NMDA）受体功能受抑制性支架蛋白RACK1调节。
NMDA receptor function is regulated by the inhibitory scaffolding protein, RACK1.
作者信息
Yaka Rami, Thornton Claire, Vagts Alicia J, Phamluong Khanhky, Bonci Antonello, Ron Dorit
机构信息
Ernest Gallo Clinic and Research Center, University of California, San Francisco, CA 94110-3518, USA.
出版信息
Proc Natl Acad Sci U S A. 2002 Apr 16;99(8):5710-5. doi: 10.1073/pnas.062046299. Epub 2002 Apr 9.
Abstract
Phosphorylation regulates the function of ligand-gated ion channels such as the N-methyl d-aspartate (NMDA) receptor. Here we report a mechanism for modulation of the phosphorylation state and function of the NMDA receptor via an inhibitory scaffolding protein, RACK1. We found that RACK1 binds both the NR2B subunit of the NMDA receptor and the nonreceptor protein tyrosine kinase, Fyn. RACK1 inhibits Fyn phosphorylation of NR2B and decreases NMDA receptor-mediated currents in CA1 hippocampal slices. Peptides that disrupt the interactions between RACK1, NR2B, and Fyn induce phosphorylation and potentiate NMDA receptor-mediated currents. Therefore, RACK1 is a regulator of NMDA receptor function and may play a role in synaptic plasticity, addiction, learning, and memory.
摘要
磷酸化作用调节配体门控离子通道的功能，比如N-甲基-D-天冬氨酸（NMDA）受体。在此我们报告一种经由抑制性支架蛋白RACK1来调节NMDA受体磷酸化状态及其功能的机制。我们发现RACK1既能结合NMDA受体的NR2B亚基，也能结合非受体蛋白酪氨酸激酶Fyn。RACK1抑制Fyn对NR2B的磷酸化作用，并降低CA1海马切片中NMDA受体介导的电流。破坏RACK1、NR2B和Fyn之间相互作用的肽会诱导磷酸化并增强NMDA受体介导的电流。因此，RACK1是NMDA受体功能的调节因子，可能在突触可塑性、成瘾、学习和记忆中发挥作用。
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本文引用的文献
1
The PTPmu protein-tyrosine phosphatase binds and recruits the scaffolding protein RACK1 to cell-cell contacts.
J Biol Chem. 2001 May 4;276(18):14896-901. doi: 10.1074/jbc.M010823200. Epub 2001 Feb 13.
2
Characterization of Fyn-mediated tyrosine phosphorylation sites on GluR epsilon 2 (NR2B) subunit of the N-methyl-D-aspartate receptor.
J Biol Chem. 2001 Jan 5;276(1):693-9. doi: 10.1074/jbc.M008085200.
3
Proteomic analysis of NMDA receptor-adhesion protein signaling complexes.
Nat Neurosci. 2000 Jul;3(7):661-9. doi: 10.1038/76615.
4
Identification of proteins in the postsynaptic density fraction by mass spectrometry.
J Neurosci. 2000 Jun 1;20(11):4069-80. doi: 10.1523/JNEUROSCI.20-11-04069.2000.
5
Phosphorylation-dependent interaction of the N-methyl-D-aspartate receptor epsilon 2 subunit with phosphatidylinositol 3-kinase.
Genes Cells. 1999 Nov;4(11):657-66. doi: 10.1046/j.1365-2443.1999.00287.x.
6
Subunit-specific association of protein kinase C and the receptor for activated C kinase with GABA type A receptors.
J Neurosci. 1999 Nov 1;19(21):9228-34. doi: 10.1523/JNEUROSCI.19-21-09228.1999.
7
Association of RACK1 and PKCbeta with the common beta-chain of the IL-5/IL-3/GM-CSF receptor.
Oncogene. 1999 Sep 9;18(36):5126-30. doi: 10.1038/sj.onc.1202896.
8
Coordinated movement of RACK1 with activated betaIIPKC.
J Biol Chem. 1999 Sep 17;274(38):27039-46. doi: 10.1074/jbc.274.38.27039.
9
Subunit- and site-specific pharmacology of the NMDA receptor channel.
Prog Neurobiol. 1999 Oct;59(3):279-98. doi: 10.1016/s0301-0082(99)00007-6.
10
Expression mechanisms underlying NMDA receptor-dependent long-term potentiation.
Ann N Y Acad Sci. 1999 Apr 30;868:515-25. doi: 10.1111/j.1749-6632.1999.tb11320.x.
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