Target validation: Weak selectivity of LY341495 for mGluR2 over mGluR4 makes glutamate a less selective agonist.
Target validation: Weak selectivity of LY341495 for mGluR2 over mGluR4 makes glutamate a less selective agonist.
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靶标验证：LY341495 对 mGluR2 的选择性较 mGluR4 弱，使得谷氨酸成为选择性较低的激动剂。
DOI：
10.1002/prp2.471
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发表时间：
2019
影响因子：
2.6
通讯作者：
Kammermeier,PaulJ
中科院分区：
文献类型：
--
作者：
McCullock,TylerW;Kammermeier,PaulJ
代谢型谷氨酸受体（Metabotropic glutamate receptor，mGluRs）是广泛表达于中枢神经系统的C类G蛋白偶联受体。哺乳动物基因组中有8个mGluR。对mGluRs的研究依赖于选择性化合物的可用性。虽然已经描述了许多选择性变构化合物，但由于mGluR家族中谷氨酸结合口袋的相似性，正构激动剂和拮抗剂的选择性更加困难。LY341495已被用作一种有效的和选择性的II组mGluR拮抗剂数十年。在此研究了LY341495在mGluR2（一种II组mGluR）和mGluR4（一种III组受体）之间的选择性，mGluR4在来自上级颈神经节（SCG）的成年大鼠交感神经元中异源表达，这提供了一个空mGluR背景，在此基础上单独检查mGluR。该化合物事实上选择性抑制mGluR2超过mGluR4，但以这样的方式，它使两种受体的信号传导更难以区分。mGluR2的谷氨酸效力比mGluR4高约10倍。50 nmol L−1LY341495没有改变mGluR4信号，但使mGluR2谷氨酸剂量反应改变了约10倍，因此它与mGluR4的剂量反应更紧密地重叠。将LY341494剂量增加至500 nmol L− 1，mGluR2的谷氨酸剂量反应进一步发生了约10倍的变化，但mGluR4的变化也类似。因此，虽然当单独应用时，谷氨酸是相对于mGluR4的mGluR2的中等选择性激动剂，但在增加浓度的LY341495存在下，谷氨酸的这种选择性丧失。
Metabotropic glutamate receptors (mGluRs) are class C G protein coupled receptors with widespread expression in the central nervous system. There are eight mGluRs in the mammalian genome. Research on mGluRs relies on the availability of selective compounds. While many selective allosteric compounds have been described, selectivity of orthosteric agonists and antagonists has been more difficult due to the similarity of the glutamate binding pocket across the mGluR family. LY341495 has been used for decades as a potent and selective group II mGluR antagonist. The selectivity of LY341495 was investigated here between mGluR2, a group II mGluR, and mGluR4, a group III receptor, heterologously expressed in adult rat sympathetic neurons from the superior cervical ganglion (SCG), which provides a null‐mGluR background upon which mGluRs were examined in isolation. The compound does in fact selectively inhibit mGluR2 over mGluR4, but in such a way that it makes signaling of the two receptors more difficult to distinguish. The glutamate potency of mGluR2 is about 10‐fold higher than mGluR4. 50 nmol L−1LY341495 did not alter mGluR4 signaling but shifted the mGluR2 glutamate dose‐response about 10‐fold, such that it overlapped more closely with that of mGluR4. Increasing the LY341494 dose to 500 nmol L−1further shifted the glutamate dose‐response of mGluR2 by another ~10‐fold, but also shifted that of mGluR4 similarly. Thus, while glutamate is a moderately selective agonist of mGluR2 over mGluR4 when applied alone, in the presence of increasing concentrations of LY341495, this selectivity of glutamate is lost.