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CELLULAR AND MOLECULAR

Activation of Metabotropic Glutamate Receptor 1 Dimers Requires Glutamate Binding in Both Subunits

Department of Physiology and Pharmacology, Northeastern Ohio Universities College of Medicine, Rootstown, Ohio

Group I metabotropic glutamate receptors (mGluRs) form stable, disulfide-linked homodimers. Lack of a verifiably monomeric mGluR1 mutant has led to difficulty in assessing the role of dimerization in the molecular mechanism of mGluR1 activation. The related GABA_B receptor exhibits striking intradimer cross talk (ligand binding at one subunit effectively produces G protein activation at the other), but it is unclear whether group I mGluRs exhibit analogous cross talk. Signaling of heterologously expressed mGluR1 was examined in isolated rat sympathetic neurons by measuring glutamate-mediated inhibition of native calcium currents. To examine mGluR1 activity when only one dimer subunit has access to glutamate ligand, wildtype mGluR1 was coexpressed with mGluR1 Y74A, a mutant with impaired glutamate binding, and the activity of the heterodimer (mutant/wild type) was examined. The mGluR1 Y74A mutant alone had a dose-response curve that was shifted by about 2 orders of magnitude. The half-maximal dose of glutamate shifted from 1.3 (wild-type mGluR1) to about 450 (mGluR1 Y74A) µM. However, the maximal effect was similar. Wild-type mGluR1 was expressed with excess Y74A mGluR1 to generate a receptor population consisting largely of mutant homodimers and mutant/wild-type heterodimers but without detectable wild-type homodimers. Under these conditions, no glutamate-mediated calcium current inhibition was observed below 300 µM glutamate, although wild-type mGluR1 protein was detectable with immunofluorescence. These data suggest that mutant/wild-type heterodimeric receptors are inactive at ligand concentrations favoring glutamate association with receptor dimers at only one subunit.

Address correspondence to: Dr. Paul J. Kammermeier, Department of Physiology and Pharmacology, Northeastern Ohio Universities College of Medicine, 4209 State Route 44, P.O. Box 95, Rootstown, OH 44272. E-mail: pjkammer{at}neoucom.edu

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