Calmodulin dynamically regulates the trafficking of the metabotropic glutamate receptor mGluR5

Ho Lee Jeong, Jinu Lee, Yeong Choi Kyu, Regine Hepp, Jae Youn Lee, Kyung Lim Mi, Mayumi Chatani-Hinze, Paul A. Roche, Goo Kim Dong, Soo Ahn Young, Hoon Kim Chul, Katherine W. Roche

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Abstract

Metabotropic glutamate receptors (mGluRs) 1-8 are G protein-coupled receptors (GPCRs) that modulate excitatory neurotransmission, neurotransmitter release, and synaptic plasticity. PKC regulates many aspects of mGluR function, including protein-protein interactions, Ca2+ signaling, and receptor desensitization. However, the mechanisms by which PKC regulates mGluR function are poorly understood. We have now identified calmodulin (CaM) as a dynamic regulator of mGluR5 trafficking. We show that the major PKC phosphorylation site on the intracellular C terminus of mGluR5 is serine 901 (S901), and phosphorylation of this residue is up-regulated in response to both receptor and PKC activation. In addition, S901 phosphorylation inhibits mGluR5 binding to CaM, decreasing mGluR5 surface expression. Furthermore, blocking PKC phosphorylation of mGluR5 on S901 dramatically affects mGluR5 signaling by prolonging Ca2+ oscillations. Thus, our data demonstrate that mGluR5 activation triggers phosphorylation of S901, thereby directly linking PKC phosphorylation, CaM binding, receptor trafficking, and downstream signaling.

Original languageEnglish
Pages (from-to)12575-12580
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number34
DOIs
Publication statusPublished - 2008 Aug 26

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Jeong, H. L., Lee, J., Kyu, Y. C., Hepp, R., Lee, J. Y., Mi, K. L., Chatani-Hinze, M., Roche, P. A., Dong, G. K., Young, S. A., Chul, H. K., & Roche, K. W. (2008). Calmodulin dynamically regulates the trafficking of the metabotropic glutamate receptor mGluR5. Proceedings of the National Academy of Sciences of the United States of America, 105(34), 12575-12580. https://doi.org/10.1073/pnas.0712033105