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Altered Expression of G_q/11 Protein Shapes mGlu1 and mGlu5 Receptor-Mediated Single Cell Inositol 1,4,5-Trisphosphate and Ca²⁺ Signaling

Department of Cell Physiology & Pharmacology, University of Leicester, Leicester, United Kingdom (P.J.A., K.W.Y., S.J.E., S.R.N., R.A.J.C.); and Psychiatry Centre of Excellence for Drug Discovery, GlaxoSmithKline, Harlow, United Kingdom (J.N.C.K.)

The metabotropic glutamate (mGlu) receptors mGlu1 and mGlu5 mediate distinct inositol 1,4,5-trisphosphate (IP₃) and Ca²⁺ signaling patterns, governed in part by differential mechanisms of feedback regulation after activation. Single cell imaging has shown that mGlu1 receptors initiate sustained elevations in IP₃ and Ca²⁺, which are sensitive to agonist concentration. In contrast, mGlu5 receptors are subject to cyclical PKC-dependent uncoupling and consequently mediate coincident IP₃ and Ca²⁺ oscillations that are largely independent of agonist concentration. In this study, we investigated the contribution of G_q/11 protein expression levels in shaping mGlu1/5 receptor-mediated IP₃ and Ca²⁺ signals, using RNA interference (RNAi). RNAi-mediated knockdown of G_q/11 almost abolished the single-cell increase in IP₃ caused by mGlu1 and mGlu5 receptor activation. For the mGlu1 receptor, this unmasked baseline Ca²⁺ oscillations that persisted even at maximal agonist concentrations. mGlu5 receptor-activated Ca²⁺ oscillations were still observed but were only initiated at high agonist concentrations. Recombinant overexpression of G_q enhanced IP₃ signals after mGlu1 and mGlu5 receptor activation. It is noteworthy that although mGlu5 receptor-mediated IP₃ and Ca²⁺ oscillations in control cells were largely insensitive to agonist concentration, increasing G_q expression converted these oscillatory signatures to sustained plateau responses in a high proportion of cells. In addition to modulating temporal Ca²⁺ signals, up- or down-regulation of G_q/11 expression alters the threshold for the concentration of glutamate at which a measurable Ca²⁺ signal could be detected. These experiments indicate that altering G_q/11 expression levels differentially affects spatiotemporal aspects of IP₃ and Ca²⁺ signaling mediated by the mGlu1 and mGlu5 receptors.

Address correspondence to: Prof. R. A. J. Challiss, Department of Cell Physiology and Pharmacology, University of Leicester, Maurice Shock Medical Sciences Building, University Road, Leicester, LE1 9HN, UK. E-mail: jc36{at}le.ac.uk

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