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PNAS 103 (4): 1124-1128

Copyright © 2006 by the National Academy of Sciences.

PHYSIOLOGY

Dual signaling is differentially activated by different active states of the metabotropic glutamate receptor 1{alpha}

Michihiro Tateyama *, {dagger}, {ddagger}, and Yoshihiro Kubo *, {dagger}, §

*Division of Biophysics and Neurobiology, Department of Molecular Physiology, National Institute for Physiological Sciences, Myodaiji, Okazaki 444-8585, Japan; {dagger}Solution Oriented Research for Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan; and§COE 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.

Abstract: 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 glutamate-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.

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.

Abbreviations: [Ca2+]i, intracellular Ca2+ concentration; mGluR1{alpha}, metabotropic glutamate receptor 1{alpha}; GPCR, G protein-coupling receptor; ECD, extracellular domain; ICD, intracellular domain; CO/A, closed–open/active; CCA, closed–closed/active; FP, fluorescent protein; 7-TM, seven-transmembrane region.

{ddagger} To whom correspondence should be addressed. E-mail: tateyama{at}nips.ac.jp.

© 2006 by The National Academy of Sciences of the USA

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