The heptahelical domain of GABAB2 is activated directly by CGP7930, a positive allosteric modulator of the GABAB receptor
The heptahelical domain of GABAB2 is activated directly by CGP7930, a positive allosteric modulator of the GABAB receptor
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DOI：
10.1074/jbc.m400930200
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发表时间：
2004-07-09
影响因子：
4.8
通讯作者：
Prézeau, L
中科院分区：
文献类型：
--
作者：
Binet, V;Brajon, C;Prézeau, L
众所周知，γ-氨基丁酸B型（GABA（B））受体由GABA（B1）和GABA（B2）两个亚基组成。这两个亚基与其他III类G蛋白偶联受体具有结构同源性。它们由两个主要结构域组成：所有G蛋白偶联受体的典型七螺旋结构域（HD）和大的胞外结构域（ECD）。虽然GABA（B1）结合GABA，但GABA（B2）是GABAB 1到达细胞表面所必需的。然而，仍然没有证明这两个亚基的联合是否总是大脑功能所必需的。事实上，GABA（B2）在异聚体与G蛋白的偶联中起主要作用，使得GABA（B2）可以在不存在GABA（B1）的情况下传递信号。目前，只有与GABA（B1）ECD相互作用的配体已被鉴定。因此，专门作用于GABA（B2）亚基的化合物将有助于分析该亚基在大脑中的具体作用。在这里，我们探讨了CGP 7930的作用机制，CGP 7930是一种被描述为GABA（B）受体的正变构调节剂的化合物。我们发现，它激活野生型GABA（B）受体，但效力较低。GABA（B2）HD是这种效应所必需的，尽管不能排除CGP 7930也可以与GABA（B1）结合。有趣的是，CGP 7930可以激活单独表达的GABA（B2），并且是第一个描述的GABA（B2）激动剂。最后，我们表明，CGP 7930保留其激动剂活性的GABA（B2）亚基删除其ECD。这表明GABA（B2）的HD表现类似于视紫红质样受体，因为它可以单独到达细胞表面，可以与G蛋白偶联，并被激动剂激活。这些结果为研究GABA（B）受体的激活机制和探讨同型GABA（B2）受体的可能作用提供了新的思路。
The gamma-aminobutyric acid, type B (GABA(B)) receptor is well recognized as being composed of two subunits, GABA(B1) and GABA(B2). Both subunits share structural homology with other class-III G-protein-coupled receptors. They are composed of two main domains: a heptahelical domain (HD) typical of all G-protein-coupled receptors and a large extracellular domain (ECD). Although GABA(B1) binds GABA, GABA(B2) is required for GABAB1 to reach the cell surface. However, it is still not demonstrated whether the association of these two subunits is always required for function in the brain. Indeed, GABA(B2) plays a major role in the coupling of the heteromer to G-proteins, such that it is possible that GABA(B2) can transmit a signal in the absence of GABA(B1). Today only ligands interacting with GABA(B1) ECD have been identified. Thus, the compounds acting exclusively on the GABA(B2) subunit will be helpful in analyzing the specific role of this subunit in the brain. Here, we explored the mechanism of action of CGP7930, a compound described as a positive allosteric regulator of the GABA(B) receptor. We showed that it activates the wild type GABA(B) receptor but with a low efficacy. The GABA(B2) HD is necessary for this effect, although one cannot exclude that CGP7930 could also bind to GABA(B1). Of interest, CGP7930 could activate GABA(B2) expressed alone and is the first described agonist of GABA(B2). Finally, we show that CGP7930 retains its agonist activity on a GABA(B2) subunit deleted of its ECD. This demonstrates that the HD of GABA(B2) behaves similar to a rhodopsin-like receptor, because it can reach the cell surface alone, can couple to G-protein, and be activated by agonists. These data open new strategies for studying the mechanism of activation of GABA(B) receptor and examine any possible role of homomeric GABA(B2) receptors.