科研之友
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摘要
The metabotropic glutamate receptor 1 alpha (mGluR1 alpha) is crucial for some forms of synaptic plasticity, by inducing various cell responses via coupling to various types of G proteins. Upon glutamate binding, an active conformation, closed-open/active, of the extracellular domain is stabilized, which induces dimeric rearrangement in the intracellular domains, resulting in the initiation of downstream signals. We have confirmed that mGluR1 alpha functionally interacts with both Gq and Gs pathways; a combination of fluorescent indicators showed that glutamate increased intracellular Ca2+ and cAMP concentration ([Ca2+](i) and [cAMP](i)). By contrast, Gd3+, a different type of ligand whose recognition site on mGluR1 alpha is distinct from the glutamate site, increased only [Ca2+](i) and the concentration-activation curve was bell-shaped. FRET analysis revealed that a low concentration of Gd3+ induced dimeric rearrangement of the intracellular domains of mGluR1 alpha as does glutamate, whereas a high concentration of Gd3+ reversed the FRET efficiency, which was consistent with a bell-shaped relationship between concentration and Gq activation. These results suggest that Gd3+ induces an active and a sort of "inactivated" conformation in mGluR1 alpha. The Gd3+-induced active state is considered to correspond to the closed-closed/active conformation, revealed by previous x-ray crystallographic studies. In conclusion, the glutarnate-induced closed-open/active state coupled both to Gs and Gq proteins whereas the Gd3+-induced closed-closed/active conformation state preferred Gq to Gs, suggesting that mGluR1 alpha serves not only as a simple on/off switch but also as a multiple signaling path regulator.
- 出版日期2006-1-24
