Metabotropic glutamate receptors (mGluRs) are a diverse and abundant class of receptors that mediate neuromodulatory actions of glutamate, the most abundant and ubiquitous transmitter in the vertebrate CNS. Based on the important role these receptors have in neuronal development, synaptic plasticity, and the modulation of synaptic transmission, it is likely that appropriate functioning of these receptors is a critical determinant in the cell biology underlying mental health and disease. To understand the molecular basis for mGluR function, we have been performing biochemical and molecular biological analyses of the structure of mGluRs, concentrating on mGluR5, a developmentally regulated receptor coupled to phosphatidylinositol hydrolysis and Ca2+ mobilization. We have recently discovered a novel feature of mGluR5 structure, that it is a disulfide-linked dimer. Moreover, there is evidence that this structural feature is shared by the other mGluRs. In order to test the hypothesis that dimerization has important functional consequences and may also be a regulated mechanism, three lines of experimentation are proposed. First, in order to elucidate the molecular basis for dimerization, cysteine residues in the mGluR5 sequence will be systematically changed to serines to identify which cysteines participate in the requisite disulfide bond(s). Moreover, because the closely related mGluR1a does not form heterodimers with mGluR5, chimeras containing increasing lengths of mGluR1a sequence in place of mGluR5 will be constructed, and their ability to dimerize with wild type mGluR5 will be assessed to determine the structural basis for this homomeric specificity. Second, to analyze the functional significance of mGluR5 dimerization, the activity of non-dimerizing, mutant receptors will be compared with wild type ones using binding assays, phosphatidylinositol turnover assays, and assays of intracellular Ca2+ mobilization. Third, to determine whether dimerization is a regulated process, the state of mGluR5 dimerization in different brain regions and at different developmental periods will be examined. Furthermore, the occurrence of dimers following procedures leading to receptor activation will be determined in primary cultures of cerebellar granule cells and transfected cell systems. By studying the basis and significance of mGluR dimerization, we will deepen our understanding of neural communication and signal transduction, processes which underlie brain function and dysfunction.

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National Institute of Mental Health (NIMH)
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Molecular, Cellular, and Developmental Neurobiology Review Committee (MCDN)
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Washington University
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Jong, Yuh-Jiin I; O'Malley, Karen L (2017) Mechanisms Associated with Activation of Intracellular Metabotropic Glutamate Receptor, mGluR5. Neurochem Res 42:166-172
Sergin, Ismail; Jong, Yuh-Jiin I; Harmon, Steven K et al. (2017) Sequences within the C Terminus of the Metabotropic Glutamate Receptor 5 (mGluR5) Are Responsible for Inner Nuclear Membrane Localization. J Biol Chem 292:3637-3655
Jong, Yuh-Jiin I; O'Malley, Karen L (2015) Functional G protein-coupled receptors on nuclei from brain and primary cultured neurons. Methods Mol Biol 1234:113-21
Jong, Yuh-Jiin I; Sergin, Ismail; Purgert, Carolyn A et al. (2014) Location-dependent signaling of the group 1 metabotropic glutamate receptor mGlu5. Mol Pharmacol 86:774-85
Kumar, Vikas; Fahey, Paul G; Jong, Yuh-Jiin I et al. (2012) Activation of intracellular metabotropic glutamate receptor 5 in striatal neurons leads to up-regulation of genes associated with sustained synaptic transmission including Arc/Arg3.1 protein. J Biol Chem 287:5412-25
Jong, Yuh-Jiin I; Kumar, Vikas; O'Malley, Karen L (2009) Intracellular metabotropic glutamate receptor 5 (mGluR5) activates signaling cascades distinct from cell surface counterparts. J Biol Chem 284:35827-38
Kumar, Vikas; Jong, Yuh-Jiin I; O'Malley, Karen L (2008) Activated nuclear metabotropic glutamate receptor mGlu5 couples to nuclear Gq/11 proteins to generate inositol 1,4,5-trisphosphate-mediated nuclear Ca2+ release. J Biol Chem 283:14072-83
Jong, Yuh-Jiin I; Schwetye, Katherine E; O'Malley, Karen L (2007) Nuclear localization of functional metabotropic glutamate receptor mGlu1 in HEK293 cells and cortical neurons: role in nuclear calcium mobilization and development. J Neurochem 101:458-69
Jong, Yuh-Jiin I; Kumar, Vikas; Kingston, Ann E et al. (2005) Functional metabotropic glutamate receptors on nuclei from brain and primary cultured striatal neurons. Role of transporters in delivering ligand. J Biol Chem 280:30469-80
Higgs, M H; Romano, C; Lukasiewicz, P D (2002) Presynaptic effects of group III metabotropic glutamate receptors on excitatory synaptic transmission in the retina. Neuroscience 115:163-72

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