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Dual signaling is differentially activated by different active states of the metabotropic glutamate receptor 1
Michihiro Tateyama *, ,, and
Yoshihiro Kubo *, ,
*Division of Biophysics and Neurobiology, Department of Molecular Physiology, National Institute for Physiological Sciences, Myodaiji, Okazaki 444-8585, Japan; Solution Oriented Research for Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan; andCOE Program for Brain Integration and Its Disorders, Tokyo Medical and Dental University, Graduate School and Faculty of Medicine, Bunkyo, Tokyo 113-8519, Japan
Edited by Lily Y. Jan, University of California School of Medicine, San Francisco, CA, and approved November 23, 2005
Received for publication July 13, 2005.
The metabotropic glutamate receptor 1 (mGluR1) is crucial forsome forms of synaptic plasticity, by inducing various cellresponses via coupling to various types of G proteins. Uponglutamate binding, an active conformation, closedopen/active,of the extracellular domain is stabilized, which induces dimericrearrangement in the intracellular domains, resulting in theinitiation of downstream signals. We have confirmed that mGluR1functionally interacts with both Gq and Gs pathways; a combinationof fluorescent indicators showed that glutamate increased intracellularCa2+ and cAMP concentration ([Ca2+]i and [cAMP]i). By contrast,Gd3+, a different type of ligand whose recognition site on mGluR1is distinct from the glutamate site, increased only [Ca2+]iand the concentration-activation curve was bell-shaped. FRETanalysis revealed that a low concentration of Gd3+ induced dimericrearrangement of the intracellular domains of mGluR1 as doesglutamate, whereas a high concentration of Gd3+ reversed theFRET efficiency, which was consistent with a bell-shaped relationshipbetween concentration and Gq activation. These results suggestthat Gd3+ induces an active and a sort of "inactivated" conformationin mGluR1. The Gd3+-induced active state is considered to correspondto the closed-closed/active conformation, revealed by previousx-ray crystallographic studies. In conclusion, the glutamate-inducedclosedopen/active state coupled both to Gs and Gq proteinswhereas the Gd3+-induced closed-closed/active conformation statepreferred Gq to Gs, suggesting that mGluR1 serves not only asa simple on/off switch but also as a multiple signaling pathregulator.
Key Words: FRET G protein-coupling receptor
Conflict of interest statement: No conflicts declared.
This paper was submitted directly (Track II) to the PNAS office.