Regulation of NMDA receptor trafficking and function by striatal-enriched tyrosine phosphatase (STEP)
Regulation of NMDA receptor trafficking and function by striatal-enriched tyrosine phosphatase (STEP)
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DOI：
10.1111/j.1460-9568.2006.04837.x
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发表时间：
2006-06-01
影响因子：
3.4
通讯作者：
Nikolich, Karoly
中科院分区：
文献类型：
--
作者：
Braithwaite, Steven P.;Adkisson, Michael;Nikolich, Karoly
N-甲基-D-天冬氨酸 (NMDA) 受体的调节对于中枢神经系统的正常功能至关重要。必须有精确的机制来允许学习和正常突触传递所需的受体功能发生变化，但要在严格的限制范围内以防止病理发生。酪氨酸磷酸化是通过 Src 家族激酶和酪氨酸磷酸酶活性之间的平衡来调节 NMDA 受体的主要手段。 NMDA 受体磷酸酶的鉴定一直很困难，最好的候选者是纹状体富集酪氨酸磷酸酶 (STEP)。在这里，我们证明 STEP 是 NMDA 受体的关键调节因子，并揭示这种酪氨酸磷酸酶的作用控制 NMDA 受体的组成型运输，并导致神经元表面 NMDA 受体活性的变化。我们证明，在没有其他突触蛋白存在的情况下，STEP 可以直接与 NMDA 受体结合。 STEP 的活性选择性地影响神经元质膜上 NMDA 受体的表达。 STEP 对 NMDA 受体的作用结果会影响受体的功能特性及其下游信号传导。当 STEP 水平长期降低时，这些影响很明显，表明磷酸酶之间没有冗余来补偿 CNS 中 STEP 功能的改变。 STEP 可能是专门进化来充当 NMDA 受体磷酸酶的关键角色，具有独特且受限的定位和区室化，以及对 NMDA 受体及其信号通路的独特活性。
Regulation of N-methyl-D-aspartate (NMDA) receptors is critical for the normal functioning of the central nervous system. There must be precise mechanisms to allow for changes in receptor function required for learning and normal synaptic transmission, but within tight constraints to prevent pathology. Tyrosine phosphorylation is a major means by which NMDA receptors are regulated through the equilibrium between activity of Src family kinases and tyrosine phosphatases. Identification of NMDA receptor phosphatases has been difficult, the best candidate being striatal-enriched tyrosine phosphatase (STEP). Here we demonstrate that STEP is a critical regulator of NMDA receptors and reveal that the action of this tyrosine phosphatase controls the constitutive trafficking of NMDA receptors and leads to changes in NMDA receptor activity at the neuronal surface. We show that STEP binds directly to NMDA receptors in the absence of other synaptic proteins. The activity of STEP selectively affects the expression of NMDA receptors at the neuronal plasma membrane. The result of STEP's action upon the NMDA receptor affects the functional properties of the receptor and its downstream signaling. These effects are evident when STEP levels are chronically reduced, indicating that there is no redundancy amongst phosphatases to compensate for altered STEP function in the CNS. STEP may have evolved specifically to fill a pivotal role as the NMDA receptor phosphatase, having a distinct and restricted localization and compartmentalization, and unique activity towards the NMDA receptor and its signaling pathway.