Tissue-type plasminogen activator requires a co-receptor to enhance NMDA receptor function
Tissue-type plasminogen activator requires a co-receptor to enhance NMDA receptor function
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DOI：
10.1111/j.1471-4159.2008.05687.x
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发表时间：
2008-11-01
影响因子：
4.7
通讯作者：
Medcalf, Robert L.
中科院分区：
文献类型：
--
作者：
Samson, Andre L.;Nevin, Simon T.;Medcalf, Robert L.
谷氨酸是中枢神经系统的主要兴奋性神经递质。组织型纤溶酶原激活剂 (tPA) 被认为是谷氨酸能神经传递的调节剂。这一属性的例证是其在谷氨酸结合 NMDA 受体 (NMDAR) 激活后增强钙信号传导的能力。据推测，tPA 可以直接裂解 NMDAR 的 NR1 亚基，从而增强 NMDA 诱导的钙内流。相比之下，我们在这里表明，NMDAR 信号传导的增加需要 tPA 具有蛋白水解活性，但不涉及 NR1 亚基或纤溶酶原的裂解。相反，我们证明 tPA 增强 NMDAR 功能是由低密度脂蛋白受体 (LDLR) 家族成员介导的。因此，本研究提出了 tPA、NMDAR、LDLR 和未知底物（我们怀疑是丝氨酸蛋白酶抑制剂）之间的新功能关系。有趣的是，虽然单独的 tPA 无法裂解 NR1，但细胞表面 NMDAR 确实可以作为纤溶酶的有效且离散的蛋白水解靶标。因此，纤溶酶和 tPA 可以通过不同的途径影响 NMDAR。总而言之，我们发现纤溶酶直接蛋白水解 NMDAR，而 tPA 通过 LDLR 参与作为 NMDA 诱导事件的间接调节剂。
Glutamate is the main excitatory neurotransmitter of the CNS. Tissue-type plasminogen activator (tPA) is recognized as a modulator of glutamatergic neurotransmission. This attribute is exemplified by its ability to potentiate calcium signaling following activation of the glutamate-binding NMDA receptor (NMDAR). It has been hypothesized that tPA can directly cleave the NR1 subunit of the NMDAR and thereby potentiate NMDA-induced calcium influx. In contrast, here we show that this increase in NMDAR signaling requires tPA to be proteolytically active, but does not involve cleavage of the NR1 subunit or plasminogen. Rather, we demonstrate that enhancement of NMDAR function by tPA is mediated by a member of the low-density lipoprotein receptor (LDLR) family. Hence, this study proposes a novel functional relationship between tPA, the NMDAR, a LDLR and an unknown substrate which we suspect to be a serpin. Interestingly, whilst tPA alone failed to cleave NR1, cell-surface NMDARs did serve as an efficient and discrete proteolytic target for plasmin. Hence, plasmin and tPA can affect the NMDAR via distinct avenues. Altogether, we find that plasmin directly proteolyses the NMDAR whilst tPA functions as an indirect modulator of NMDA-induced events via LDLR engagement.