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.
Signaling by the metabotropic glutamate receptor 1alpha (mGluR1alpha) can lead to the accumulation of inositol 1,4, 5-trisphosphate (InsP(3)) and cAMP and to the modulation of K(+) and Ca(2+) 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 InsP(3) 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 mGluR1alpha-dependent signaling pathways. PKC activation selectively inhibits agonist-dependent stimulation of the InsP(3) pathway but does not affect receptor signaling via cAMP. In contrast, protein kinase A potentiates agonist-independent signaling of the receptor via InsP(3). 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 Thr(695) selectively disrupts mGluR1alpha-G(q/11) interaction without affecting signaling through G(s). 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.
Francesconi
A
A
Department of Ophthalmology, Margaret M. Dyson Vision Research Institute, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021, USA. afrance@med.cornell.edu
Duvoisin
R M
RM
D000494:Allosteric Regulation; D000595:Amino Acid Sequence; D000818:Animals; D020013:Calcium Signaling / Q000502:physiology*; D000242:Cyclic AMP / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism*; D015544:Inositol 1,4,5-Trisphosphate / Q000502:physiology*; D017136:Ion Transport; D008969:Molecular Sequence Data; D009865:Oocytes; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D010769:Phosphothreonine / Q000032:analysis; D011493:Protein Kinase C / Q000502:physiology*; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D018094:Receptors, Metabotropic Glutamate / Q000737:chemistry / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D014162:Transfection; D014982:Xenopus laevis
D018094:Receptors, Metabotropic Glutamate; D011993:Recombinant Fusion Proteins; D010769:Phosphothreonine; D015544:Inositol 1,4,5-Trisphosphate; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D020962:Heterotrimeric GTP-Binding Proteins