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J. Biol. Chem., Vol. 283, Issue 36, 24300-24307, September 5, 2008

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Increases in Intracellular Calcium Triggered by Channelrhodopsin-2 Potentiate the Response of Metabotropic Glutamate Receptor mGluR7^*

John H. Caldwell¹², Greta Ann Herin¹³, Georg Nagel^¶||, Ernst Bamberg^¶, Astrid Scheschonka, and Heinrich Betz

From the Department of Neurochemistry, Max-Planck-Institute for Brain Research, D-60528 Frankfurt am Main, Germany, the Department of Cell and Developmental Biology, University of Colorado Health Sciences Center, Aurora, Colorado 80045, the ^¶Max-Planck-Institute for Biophysics, D-60438 Frankfurt am Main, Germany, and the ^||University of Würzburg, D-97082 Würzburg, Germany

The metabotropic glutamate receptor 7a (mGluR7a), a heptahelical G_i/o-coupled protein, has been shown to be important for presynaptic feedback inhibition at central synapses and certain forms of long term potentiation and long term depression. The intracellular C terminus of mGluR7a interacts with calmodulin in a Ca²⁺-dependent manner, and calmodulin antagonists have been found to abolish presynaptic inhibition of glutamate release in neurons and mGluR7a-induced activation of G-protein-activated inwardly rectifying K⁺ channel (GIRK) channels in HEK293 cells. Here, we characterized the Ca²⁺ dependence of mGluR7a signaling in Xenopus oocytes by using channelrhodopsin-2 (ChR2), a Ca²⁺-permeable, light-activated ion channel for triggering Ca²⁺ influx, and a GIRK3.1/3.2 concatemer to monitor mGluR7a responses. Application of the agonist (S)-2-amino-4-phosphonobutanoic acid (L-AP4) (1–100 µM) caused a dose-dependent inward current in high K⁺ solutions due to activation of GIRK channels by G-protein β subunits released from mGluR7a. Elevation of intracellular free Ca²⁺ by light stimulation of ChR2 markedly increased the amplitude of L-AP4 responses, and this effect was attenuated by the calcium chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis (acetoxymethyl ester). L-AP4 responses were potentiated by submembranous [Ca²⁺] levels within physiological ranges and with a threshold close to resting [Ca²⁺]_i values, as determined by recording the endogenous Xenopus Ca²⁺-activated chloride conductance. Together, these results show that L-AP4-dependent mGluR7a signaling is potentiated by physiological levels of [Ca²⁺]_i, consistent with a model in which presynaptic mGluR7a acts as a coincidence detector of Ca²⁺ influx and glutamate release.

Received for publication, April 3, 2008 , and in revised form, June 4, 2008.

^* This work was supported in part by National Institutes of Health Grant R01 26505 (to J. H. C.). Primary support for the work was from grants from Max-Planck-Gesellschaft, European Community Grant QLG3-CT-2001-00929, and Fonds der Chemischen Industrie (to H. B.) and Deutsche Forschungsgemeinschaft (Grants SFB 472/P1 and DFG-NA207/6)(to G. N.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

³ Present address: Dept. of Biology, Eastern Mennonite University, Harrisonburg, VA 22802.

² To whom correspondence should be addressed: Dept. of Cell and Developmental Biology, Mail Stop 8315, P. O. Box 6511, Aurora, CO 80045. Tel.: 303-724-3190; Fax: 303-724-3121; E-mail: john.caldwell{at}uchsc.edu.

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