蛋白质棕榈酰化对离子型谷氨酸受体运输的调节作用

Regulation of the Ionotropic Glutamate Receptor Trafficking by Protein Palmitoylation

棕榈酰化是一种可逆的翻译后修饰,其对蛋白质的定位和功能具有重要的调节意义.离子型谷氨酸受体有N-甲基-D-天冬氨酸(NMDA)受体、α-氨基羟甲基恶唑丙酸(AMPA)受体和人海藻酸受体.近期研究发现,它们的棕榈酰化修饰对其膜表面分布和内化均具有重要的意义.其中NMDA受体在其C末端有2个不同的棕榈酰化位点.1个位于C末端近膜区(CysclusterⅠ),它的棕榈酰化可以增高酪氨酸的磷酸化水平,增加受体膜表面分布,影响神经元中NMDA受体的组构性内化;另1个位于C末端中部(CysclusterⅡ),它受到蛋白质酰基转移酶GODZ的调节,使得受体在高尔基体大量积聚,从而影响受体的膜表面分布.与NMDA受体相似,AMPA受体也存在2个棕榈酰化位点.1个位于在第2跨膜域,受蛋白质酰基转移酶GODZ的调节,能导致AMPA受体在高尔基体的积聚.另1个位点在受体C末端近膜区,它的棕榈酰化能降低AMPA受体和4.1N蛋白的相互作用,并调节受体的内化.这两种离子型谷氨酸受体在棕榈酰化机制上虽然存在差异,但均对受体的运输、膜表面分布和内化具有十分重要的作用.

Post-translation palmitoylation is a reversible modification regulating protein trafficking and localization from different aspects. The ionotropic glutamate receptors （ GluRs） can be classified into several groups： N-methyl-D-aspartate （NMDA）,α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid （AMPA） and KA receptors. The palmitoylation of the receptors contributes to stabilization of their surface distribution and internalization. The NMDA receptor subunits NR2A and NR2B have two palmitoylation sites of distinct clusters in the C-terminal region. The palmitoylation of Cys cluster Ⅰ on a membrane-proximal region increases tyrosine phosphorylation to enhance the stable surface expression of NMDA receptors and regulates their constitutive internalization in developing neurons. The Cys cluster Ⅱ site in the middle of C-terminal region is up-regulated by specific palmityl acyl transferases GODZ and leads to the accumulation of the receptors in the Glogi apparatus and reduces the receptor surface localization. Similarly,the AMPA receptor subunits GluR1-4 also have two different palmitoylation sites. The one palmtoylated by GODZ in the TMD 2 region retains the AMPA receptors in Glogi,and the other in the C-teminus affects the receptor internalization by AMPA and NMDA induction by weakening the interaction of the AMPA with the 4. 1N protein. . The different mechanisms underlying the palmitoylation- nonpalmitoylation of NMDA and AMPA receptors both influence the receptor trafficking, surface distribution and internalization.