A novel ubiquitously expressed α-latrotoxin receptor is a member of the CIRL family of G-protein-coupled receptors
A novel ubiquitously expressed α-latrotoxin receptor is a member of the CIRL family of G-protein-coupled receptors
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DOI：
10.1074/jbc.274.9.5491
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发表时间：
1999-02-26
影响因子：
4.8
通讯作者：
Petrenko, AG
中科院分区：
文献类型：
--
作者：
Ichtchenko, K;Bittner, MA;Petrenko, AG
黑寡妇毒素是一种来自黑寡妇蜘蛛毒液的神经毒性蛋白，它会导致自发突触传递的强烈增加和随后受影响的神经末梢的退化。α -latrotoxin的神经毒性作用首先涉及与其高亲和受体的细胞外结合。其中一种蛋白质，GIRL，是一种神经元g蛋白偶联受体，参与分泌调节。我们现在证明了GIRL有两个相似的同源基因，具有相似的结构域和高度的整体同一性。这些新的受体，我们建议命名为CIRL-2和CIRL-3，与CIRL （CIRL-1）一起属于最近发现的大型孤儿受体亚家族，具有g蛋白偶联受体和细胞粘附蛋白的典型结构特征。Northern blotting实验表明，CIRL-2在胎盘、肾脏、脾脏、卵巢、心脏和肺中普遍表达，其浓度最高，而CIRL-3与CIRL-1相似，主要在脑中表达。似乎CIRL-2也可以结合α -毒素，尽管其对毒素的亲和力约为CIRL-1的14倍，当CIRL-1在染色质细胞中过表达时。CIRL-2增加了它们对α -latrotoxin刺激的敏感性，但也抑制Ca2+调节的分泌，因此，CIRL-2是α -latrotoxin的功能受体。我们的研究结果表明，尽管神经系统是低剂量α -latrotoxin的主要靶点，但由于α -latrotoxin的低亲和力受体CIRL-2的存在，其他组织的细胞也容易受到α -latrotoxin的毒性作用。
Poisoning with alpha-latrotoxin, a neurotoxic protein from black widow spider venom, results in a robust increase of spontaneous synaptic transmission and subsequent degeneration of affected nerve terminals. The neurotoxic action of alpha-latrotoxin involves extracellular binding to its high affinity receptors as a first step. One of these proteins, GIRL, is a neuronal G-protein-coupled receptor implicated in the regulation of secretion. We now demonstrate that GIRL has two close homologs with a similar domain structure and high degree of overall identity. These novel receptors, which we propose to name CIRL-2 and CIRL-3, together with CIRL (CIRL-1) belong to a recently identified subfamily of large orphan receptors with structural features typical of both G-protein-coupled receptors and cell adhesion proteins. Northern blotting experiments indicate that CIRL-2 is expressed ubiquitously with highest concentrations found in placenta, kidney, spleen, ovary, heart, and lung whereas CIRL-3 is expressed predominantly in brain similarly to CIRL-1, It appears that CIRL-2 can also bind alpha-latrotoxin, although its affinity to the toxin is about 14 times less than that of CIRL-1, When overexpressed in chromaffin cells, CIRL-2 increases their sensitivity to alpha-latrotoxin stimulation but also inhibits Ca2+-regulated secretion, Thus, CIRL-2 is a functionally competent receptor of alpha-latrotoxin. Our findings suggest that although the nervous system is the primary target of low doses of alpha-latrotoxin, cells of other tissues are also susceptible to the toxic effects of alpha-latrotoxin because of the presence of CIRL-2, a low affinity receptor of the toxin.