α-latrotoxin receptor CIRL/latrophilin 1 (CL1) defines an unusual family of ubiquitous G-protein-linked receptors -: G-protein coupling not required for triggering exocytosis
α-latrotoxin receptor CIRL/latrophilin 1 (CL1) defines an unusual family of ubiquitous G-protein-linked receptors -: G-protein coupling not required for triggering exocytosis
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DOI：
10.1074/jbc.273.49.32715
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发表时间：
1998-12-04
影响因子：
4.8
通讯作者：
Südhof, TC
中科院分区：
文献类型：
--
作者：
Sugita, S;Ichtchenko, K;Südhof, TC
α-latrotoxin是一种有效的兴奋性神经毒素，与两种受体结合：称为CIRL/latrophilin 1（CL1）的G蛋白偶联受体和称为neurexin I α的细胞表面蛋白。我们现在表明，CL1属于一个家庭的密切相关的受体称为CL1，CL2和CL3，CLs表现出一个不寻常的多结构域的结构与类似的选择性剪接和大的额外和细胞内的序列，CLs共享域与其他G-蛋白偶联受体，凝集素，和olfactomedins/myocilin。此外，CL还含有一个新颖的、广泛存在的富含半胱氨酸的结构域，该结构域可能在CL转运至细胞表面期间指导CL的内切蛋白水解加工。虽然CL的mRNA在脑中富集，但CL在所有组织中普遍表达。为了研究α-latrotoxin与CL1的结合如何触发胞吐作用，我们使用了用人生长激素转染的PC12细胞。Ca2+依赖性分泌的人生长激素从转染的PC12细胞触发KCl去极化或α-latrotoxin和破伤风毒素和氧化苯胂，磷酸肌醇激酶抑制剂抑制。当CL1转染到PC12细胞中时，它们对α-latrotoxin的反应显着增敏。用CL1的不同剪接变体观察到对α-latrotoxin的类似致敏作用，而CL2和CL3在该测定中无活性。一个截短形式的CL1，只包含一个单一的跨膜区，大概是无法介导G蛋白信号是作为积极的野生型CL1 α-latrotoxin触发胞吐。我们的数据表明，CL1，CL2和CL3在细胞信号传导中作为G蛋白偶联受体执行一般和普遍的功能。此外，CL 1作为α-latrotoxin受体发挥专门作用，其不需要G蛋白信号传导来触发胞吐作用。这表明作为α-latrotoxin受体，CL 1募集α-latrotoxin靶向膜而不直接参与胞吐作用。
alpha-Latrotoxin, a potent excitatory neurotoxin, binds to two receptors: a G-protein-coupled receptor called CIRL/latrophilin 1 (CL1) and a cell-surface protein called neurexin I alpha. We now show that CL1 belongs to a family of closely related receptors called CL1, CL2, and CL3, CLs exhibit an unusual multidomain structure with similar alternative splicing and large extra- and intracellular sequences, CLs share domains with other G-protein-coupled receptors, lectins, and olfactomedins/myocilin. In addition, CLs contain a novel, widespread cysteine-rich domain that may direct endoproteolytic processing of CLs during transport to the cell surface. Although the mRNAs for CLs are enriched in brain, CLs are ubiquitously expressed in all tissues. To examine how binding of alpha-latrotoxin to CL1 triggers exocytosis, we used PC12 cells transfected with human growth hormone. Ca2+-dependent secretion of human growth hormone from transfected PC12 cells was triggered by KCl depolarization or alpha-latrotoxin and was inhibited by tetanus toxin and by phenylarsine oxide, a phosphoinositide kinase inhibitor. When CL1 was transfected into PC12 cells, their response to alpha-latrotoxin was sensitized dramatically. A similar sensitization to alpha-latrotoxin was observed with different splice variants of CL1, whereas CL2 and CL3 were inactive in this assay. A truncated form of CL1 that contains only a single transmembrane region and presumably is unable to mediate G-protein-signaling was as active as wild type CL1 in alpha-latrotoxin-triggered exocytosis. Our data show that CL1, CL2, and CL3 perform a general and ubiquitous function as G-protein-coupled receptors in cellular signaling. In addition, CL1 serves a specialized role as an alpha-latrotoxin receptor that does not require G-protein-signaling for triggering exocytosis, This suggests that as an alpha-latrotoxin receptor, CL1 recruits alpha-latrotoxin to target membranes without participating in exocytosis directly.