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PNAS 97 (11): 6185-6190

Copyright © 2000 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / NEUROBIOLOGY

Opposing effects of protein kinase C and protein kinase A on metabotropic glutamate receptor signaling: Selective desensitization of the inositol trisphosphate/Ca2+ pathway by phosphorylation of the receptor-G protein-coupling domain

Anna Francesconi*,{dagger} Robert M. Duvoisin{dagger},{ddagger}

Departments of {dagger}Ophthalmology and {ddagger}Cell Biology, Margaret M. Dyson Vision Research Institute, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021

Accepted for publication March 20, 2000.

Received for publication July 27, 1999.

Abstract: Signaling by the metabotropic glutamate receptor 1α (mGluR1α) can lead to the accumulation of inositol 1,4,5-trisphosphate (InsP3) and cAMP and to the modulation of K+ and Ca2+ channel opening. At present, very little is known about how these different actions are integrated and eventually turned off. Unraveling the molecular mechanisms underlying these functions is crucial for understanding mGluR-mediated regulation of synaptic transmission. It has been shown that receptor-induced activation of the InsP3 pathway is subject to feedback inhibition mediated by protein kinase C (PKC). In this study, we provide evidence for a differential regulation by PKC and protein kinase A of two distinct mGluR1α-dependent signaling pathways. PKC activation selectively inhibits agonist-dependent stimulation of the InsP3 pathway but does not affect receptor signaling via cAMP. In contrast, protein kinase A potentiates agonist-independent signaling of the receptor via InsP3. Furthermore, we demonstrate that the selectivity of PKC action on receptor signaling rests on phosphorylation of a threonine residue located in the G protein-interacting domain of the receptor. Modification at Thr695 selectively disrupts mGluR1α–Gq/11 interaction without affecting signaling through Gs. Together, these data provide insight on the mechanisms by which selective down-regulation of a specific receptor-dependent signaling pathway can be achieved and on how cross-talk between different second messenger cascades may contribute to fine-tune short- and long-term receptor activity.

* To whom reprint requests should be addressed at: Margaret M. Dyson Vision Research Institute, Weill Medical College of Cornell University, Box 233, Room LC-305, 1300 York Avenue, New York, NY 10021. E-mail: afrance{at}med.cornell.edu.

Communicated by Stephen F. Heinemann, The Salk Institute for Biological Studies, La Jolla, CA

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