The orthosteric agonist 2-chloro-5-hydroxyphenylglycine activates mGluR5 and mGluR1 with similar efficacy and potency.
The orthosteric agonist 2-chloro-5-hydroxyphenylglycine activates mGluR5 and mGluR1 with similar efficacy and potency.
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DOI：
10.1186/1471-2210-12-6
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发表时间：
2012-05-29
期刊：
影响因子：
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通讯作者：
Kammermeier PJ
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文献类型：
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作者：
Kammermeier PJ
化合物2-氯-5-羟基苯甘氨酸（CHPG）（代谢型谷氨酸受体5（mGluR 5）的名义上选择性激动剂）的功效、效力和选择性用选择的mGluR通过检测它们诱导来自大鼠上级颈神经节（SCG）的分离的交感神经元中的天然电压依赖性离子通道的调节的能力来检测。SCG神经元提供了一个空的mGluR背景，其中特定的mGluR亚型可以通过核内cDNA注射来表达。与之前的报道一致，CHPG强烈激活SCG神经元中表达的mGluR 5 b，表观EC 50约为60 μM。令人惊讶的是，当钙电流抑制被用作受体功能的测定时，CHPG也激活了两种mGluR 1剪接变体，其效力与mGluR 5相似。在表达mGluR 2或mGluR 4的细胞中未观察到1 mM CHPG的作用，表明CHPG仅激活I组mGluR（mGluR 1和5）。CHPG也能够通过mGluR 1诱导M型钾电流的调节，但不如谷氨酸那么一致。由于该通道通过Gq依赖性途径进行调节，因此这些数据表明CHPG可能对mGluR 1表现出一些偏向性激动剂特性。对电压非依赖性、Gq介导的mGluR诱导的钙电流调制数据的进一步研究证实，一些偏倚激动作用是明显的，但这种作用很弱且不一致。这些数据与表明CHPG是选择性mGluR 5激动剂的已建立文献形成对比。相反，CHPG似乎作为mGluR 1的激动剂同样有效。虽然CHPG作用于mGluR 1而非mGluR 5时观察到一些弱的偏倚激动作用，有利于Gi/o信号传导而非Gq/11，但这种作用似乎不足以完全解释文献中的差异。
The efficacy, potency, and selectivity of the compound 2-Chloro-5-hydroxyphenylglycine (CHPG), a nominally selective agonist for metabotropic glutamate receptor 5 (mGluR5), were examined with select mGluRs by examining their ability to induce modulation of the native voltage dependent ion channels in isolated sympathetic neurons from the rat superior cervical ganglion (SCG). SCG neurons offer a null mGluR-background in which specific mGluR subtypes can be made to express via intranuclear cDNA injection. Consistent with previous reports, CHPG strongly activated mGluR5b expressed in SCG neurons with an apparent EC50 around 60 μM. Surprisingly, CHPG also activated two mGluR1 splice variants with a similar potency as at mGluR5 when calcium current inhibition was used as an assay for receptor function. No effect of 1 mM CHPG was seen in cells expressing mGluR2 or mGluR4, suggesting that CHPG only activates group I mGluRs (mGluR1 and 5). CHPG was also able to induce modulation of M-type potassium current through mGluR1, but not as consistently as glutamate. Since this channel is modulated through a Gq-dependent pathway, these data indicate that CHPG may exhibit some biased agonist properties on mGluR1. Closer examination of the voltage-independent, Gq-mediated component of mGluR-induced calcium current modulation data confirmed that some biased agonism was evident, but the effect was weak and inconsistent. These data contrast with the established literature which suggests that CHPG is a selective mGluR5 agonist. Instead, CHPG appears to act equally well as an agonist at mGluR1. While some weak biased agonism was observed with CHPG acting on mGluR1, but not mGluR5, favoring Gi/o signaling over Gq/11, this effect does not appear sufficient to fully explain the discrepancies in the literature.