Constitutive activity of metabotropic glutamate receptor 7.
Constitutive activity of metabotropic glutamate receptor 7.
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DOI：
10.1186/s12868-015-0154-6
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发表时间：
2015-03-24
期刊：
影响因子：
2.4
通讯作者：
Kammermeier PJ
中科院分区：
文献类型：
--
作者：
Kammermeier PJ
代谢型谷氨酸受体（mGluRs）是广泛表达于中枢神经系统的C类G蛋白偶联受体。mGluR 7是该家族的成员，其已经涉及许多生理和病理过程，但是mGluR 7对于谷氨酸（其天然配体）的非常低的效力引起了关于其生理作用的性质的问题。在这里，证据是使用异源表达的交感神经元从大鼠上级颈神经节（SCG）和天然SCG钙电流的调制作为受体信号传导的测定，即mGluR 7表现出组成型活性。在不存在配体的情况下，该活性可作为基础钙通道调节检测到，这在未转染的细胞或用mGluR家族的其他成员转染的细胞中未观察到。此外，该基础通道调节被mGluR 7反向激动剂MMPIP可逆地抑制。令人惊讶的是，MMPIP没有强烈抑制激动剂诱导的mGluR 7活化。最后，选择性mGluR 8激动剂（R，S）-PPG也能够作为mGluR 7的反向激动剂。这些发现为mGluR 7在神经系统中引入了一种新的潜在生理作用，即组成型活性受体的作用，从而提出了一种模型，其中mGluR 7信号传导可能是有影响的，而不需要通过毫摩尔浓度的细胞外谷氨酸引起强烈的受体激活。mGluR 7的组成型活性可能被其他III组mGluR的存在消除或降低，这可能是由于异源二聚体的形成。此外，MMPIP和PPG均充当mGluR 7的反向激动剂和mGluR 8的激动剂。
Metabotropic glutamate receptors (mGluRs) are class C G protein coupled receptors with widespread central nervous system expression. mGluR7 is a member of this family that has been implicated in numerous physiological and pathological processes, but the very low potency of mGluR7 for glutamate, its natural ligand, raise questions about the nature of its physiological role. Here, evidence is presented using heterologous expression in sympathetic neurons from the rat superior cervical ganglion (SCG) and modulation of the native SCG calcium currents as an assay for receptor signaling, that mGluR7 exhibits constitutive activity. This activity is detectable as basal calcium channel modulation in the absence of ligand that is not observed in untransfected cells or those transfected with other members of the mGluR family. Further, this basal channel modulation was reversibly inhibited with the mGluR7 inverse agonist MMPIP. Surprisingly, MMPIP did not strongly inhibit agonist-induced mGluR7 activation. Finally, the selective mGluR8 agonist (R,S)-PPG was also able to act as an inverse agonist at mGluR7. These findings introduce a novel potential physiological role for mGluR7 in the nervous system, that of a constitutively active receptor, and thereby suggest a model in which mGluR7 signaling may be impactful without the need to invoke strong receptor activation by millimolar concentrations of extracellular glutamate. Constitutive activity of mGluR7 may be eliminated or reduced by the presence of other group III mGluRs, perhaps due to heterodimer formation. In addition, both MMPIP and PPG acted as inverse agonists at mGluR7, and agonists at mGluR8.
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DOI：
10.1124/jpet.107.124701
发表时间：
2007-10-01
影响因子：
3.5
作者：
Suzuki, Gentaroh;Tsukamoto, Naohiro;Ohta, Hisashi
通讯作者：
Ohta, Hisashi
影响因子：
4.7
作者：
BENVENISTE, H;DREJER, J;DIEMER, NH
通讯作者：
DIEMER, NH
影响因子：
2.5
作者：
ZHU, Y;IKEDA, SR
通讯作者：
IKEDA, SR
影响因子：
64.8
作者：
BEAN, BP
通讯作者：
BEAN, BP
影响因子：
64.8
作者：
DeWaard, M;Liu, HY;Campbell, KP
通讯作者：
Campbell, KP