Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

PNAS 97 (11): 6185-6190

Copyright © 2000 by the National Academy of Sciences.


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}

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

Systematic analysis of somatic mutations in phosphorylation signaling predicts novel cancer drivers.
J. Reimand and G. D. Bader (2014)
Mol Syst Biol 9, 637
   Abstract »    Full Text »    PDF »
Somatic Mutations in GRM1 in Cancer Alter Metabotropic Glutamate Receptor 1 Intracellular Localization and Signaling.
J. L. Esseltine, M. D. Willard, I. H. Wulur, M. E. Lajiness, T. D. Barber, and S. S. G. Ferguson (2013)
Mol. Pharmacol. 83, 770-780
   Abstract »    Full Text »    PDF »
Phosphorylation and Feedback Regulation of Metabotropic Glutamate Receptor 1 by Calcium/Calmodulin-Dependent Protein Kinase II.
D.-Z. Jin, M.-L. Guo, B. Xue, E. E. Fibuch, E. S. Choe, L.-M. Mao, and J. Q. Wang (2013)
J. Neurosci. 33, 3402-3412
   Abstract »    Full Text »    PDF »
Rab8 Modulates Metabotropic Glutamate Receptor Subtype 1 Intracellular Trafficking and Signaling in a Protein Kinase C-Dependent Manner.
J. L. Esseltine, F. M. Ribeiro, and S. S. G. Ferguson (2012)
J. Neurosci. 32, 16933-16942
   Abstract »    Full Text »    PDF »
Time-Dependent Cross Talk between Spinal Serotonin 5-HT2A Receptor and mGluR1 Subserves Spinal Hyperexcitability and Neuropathic Pain after Nerve Injury.
Z. Aira, I. Buesa, M. Gallego, G. Garcia del Cano, N. Mendiable, J. Mingo, D. Rada, J. Bilbao, M. Zimmermann, and J. J. Azkue (2012)
J. Neurosci. 32, 13568-13581
   Abstract »    Full Text »    PDF »
Genetic Deletion of p90 Ribosomal S6 Kinase 2 Alters Patterns of 5-Hydroxytryptamine2A Serotonin Receptor Functional Selectivity.
R. T. Strachan, N. Sciaky, M. R. Cronan, W. K. Kroeze, and B. L. Roth (2010)
Mol. Pharmacol. 77, 327-338
   Abstract »    Full Text »    PDF »
Metabotropic Glutamate 1 Receptor: Current Concepts and Perspectives.
F. Ferraguti, L. Crepaldi, and F. Nicoletti (2008)
Pharmacol. Rev. 60, 536-581
   Abstract »    Full Text »    PDF »
Dynamic Regulation of Cystic Fibrosis Transmembrane Conductance Regulator by Competitive Interactions of Molecular Adaptors.
J. H. Lee, W. Richter, W. Namkung, K. H. Kim, E. Kim, M. Conti, and M. G. Lee (2007)
J. Biol. Chem. 282, 10414-10422
   Abstract »    Full Text »    PDF »
Mechanisms Underlying Type I mGluR-Induced Activation of Lobster Gastric Mill Neurons.
R. Levi and A. I. Selverston (2006)
J Neurophysiol 96, 3378-3388
   Abstract »    Full Text »    PDF »
Phosphorylation of Protein Phosphatase Inhibitor-1 by Protein Kinase C.
B. Sahin, H. Shu, J. Fernandez, A. El-Armouche, J. D. Molkentin, A. C. Nairn, and J. A. Bibb (2006)
J. Biol. Chem. 281, 24322-24335
   Abstract »    Full Text »    PDF »
The Metabotropic Glutamate G-protein-coupled Receptors mGluR3 and mGluR1a Are Voltage-sensitive.
L. Ohana, O. Barchad, I. Parnas, and H. Parnas (2006)
J. Biol. Chem. 281, 24204-24215
   Abstract »    Full Text »    PDF »
Dual signaling is differentially activated by different active states of the metabotropic glutamate receptor 1{alpha}.
M. Tateyama and Y. Kubo (2006)
PNAS 103, 1124-1128
   Abstract »    Full Text »    PDF »
Protein Kinase C Phosphorylation of the Metabotropic Glutamate Receptor mGluR5 on Serine 839 Regulates Ca2+ Oscillations.
C. H. Kim, S. Braud, J. T. R. Isaac, and K. W. Roche (2005)
J. Biol. Chem. 280, 25409-25415
   Abstract »    Full Text »    PDF »
Retroinhibition of Presynaptic Ca2+ Currents by Endocannabinoids Released via Postsynaptic mGluR Activation at a Calyx Synapse.
C. Kushmerick, G. D. Price, H. Taschenberger, N. Puente, R. Renden, J. I. Wadiche, R. M. Duvoisin, P. Grandes, and H. von Gersdorff (2004)
J. Neurosci. 24, 5955-5965
   Abstract »    Full Text »    PDF »
Activation of Cyclic AMP-Dependent Protein Kinase Inhibits the Desensitization and Internalization of Metabotropic Glutamate Receptors 1a and 1b.
S. J. Mundell, G. Pula, J. C. A. More, D. E. Jane, P. J. Roberts, and E. Kelly (2004)
Mol. Pharmacol. 65, 1507-1516
   Abstract »    Full Text »    PDF »
Long-term modulation of mitochondrial Ca2+ signals by protein kinase C isozymes.
P. Pinton, S. Leo, M. R. Wieckowski, G. Di Benedetto, and R. Rizzuto (2004)
J. Cell Biol. 165, 223-232
   Abstract »    Full Text »    PDF »
Group I Metabotropic Glutamate Receptors Bind to Protein Phosphatase 1C: MAPPING AND MODELING OF INTERACTING SEQUENCES.
C. Croci, H. Sticht, J. H. Brandstatter, and R. Enz (2003)
J. Biol. Chem. 278, 50682-50690
   Abstract »    Full Text »    PDF »
Membrane Topology of a Metabotropic Glutamate Receptor.
G. Bhave, B. M. Nadin, D. J. Brasier, K. S. Glauner, R. D. Shah, S. F. Heinemann, F. Karim, and R. W. Gereau IV (2003)
J. Biol. Chem. 278, 30294-30301
   Abstract »    Full Text »    PDF »
Mitochondrial Ca2+ Uptake Requires Sustained Ca2+ Release from the Endoplasmic Reticulum.
G. Szabadkai, A. M. Simoni, and R. Rizzuto (2003)
J. Biol. Chem. 278, 15153-15161
   Abstract »    Full Text »    PDF »
Distinct Functional Roles of the Metabotropic Glutamate Receptors 1 and 5 in the Rat Globus Pallidus.
O. V. Poisik, G. Mannaioni, S. Traynelis, Y. Smith, and P. J. Conn (2003)
J. Neurosci. 23, 122-130
   Abstract »    Full Text »    PDF »
Anaesthetic actions on other targets:protein kinase C and guanine nucleotide-binding proteins.
M. J. Rebecchi and S. N. Pentyala (2002)
Br. J. Anaesth. 89, 62-78
   Abstract »    Full Text »    PDF »
Metabotropic Glutamate Receptor 1 Internalization Induced by Muscarinic Acetylcholine Receptor Activation: Differential Dependency of Internalization of Splice Variants on Nonvisual Arrestins.
S. J. Mundell, A.-L. Matharu, G. Pula, D. Holman, P. J. Roberts, and E. Kelly (2002)
Mol. Pharmacol. 61, 1114-1123
   Abstract »    Full Text »    PDF »
Direct Phosphorylation of Capsaicin Receptor VR1 by Protein Kinase Cepsilon and Identification of Two Target Serine Residues.
M. Numazaki, T. Tominaga, H. Toyooka, and M. Tominaga (2002)
J. Biol. Chem. 277, 13375-13378
   Abstract »    Full Text »    PDF »
Desensitization of Group I Metabotropic Glutamate Receptors in Rat Sympathetic Neurons.
P. J. Kammermeier and S. R. Ikeda (2002)
J Neurophysiol 87, 1669-1676
   Abstract »    Full Text »    PDF »
A critical protein kinase C phosphorylation site on the 5-HT1A receptor controlling coupling to N-type calcium channels.
X Wu, N Kushwaha, P R Albert, and N J Penington (2002)
J. Physiol. 538, 41-51
   Abstract »    Full Text »    PDF »
Differences in Rapid Desensitization of 5-Hydroxytryptamine2A and 5-Hydroxytryptamine2C Receptor-Mediated Phospholipase C Activation.
K. A. Berg, B. D. Stout, S. Maayani, and W. P. Clarke (2001)
J. Pharmacol. Exp. Ther. 299, 593-602
   Abstract »    Full Text »    PDF »
The Neurokinin A Receptor Activates Calcium and cAMP Responses through Distinct Conformational States.
T. Palanche, B. Ilien, S. Zoffmann, M.-P. Reck, B. Bucher, S. J. Edelstein, and J.-L. Galzi (2001)
J. Biol. Chem. 276, 34853-34861
   Abstract »    Full Text »    PDF »
A critical protein kinase C phosphorylation site on the 5-HT1A receptor controlling coupling to N-type calcium channels.
X Wu, N Kushwaha, P R Albert, and N J Penington (2002)
J. Physiol. 538, 41-51
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882