title: Protein kinase A directly phosphorylates metabotropic glutamate receptor 5 to modulate its function.
abstract: Metabotropic glutamate receptor 5 (mGluR5) regulates excitatory post-synaptic signaling in the central nervous system (CNS) and is implicated in various CNS disorders. Protein kinase A (PKA) signaling is known to play a critical role in neuropsychiatric disorders such as Parkinson's disease, schizophrenia, and addiction. Dopamine signaling is known to modulate the properties of mGluR5 in a cAMP- and PKA-dependent manner, suggesting that mGluR5 may be a direct target for PKA. Our study identifies mGluR5 at Ser870 as a direct substrate for PKA phosphorylation and demonstrates that this phosphorylation plays a critical role in the PKA-mediated modulation of mGluR5 functions such as extracellular signal-regulated kinase phosphorylation and intracellular Ca(2+) oscillations. The identification of the molecular mechanism by which PKA signaling modulates mGluR5-mediated cellular responses contributes to the understanding of the interaction between dopaminergic and glutamatergic neuronal signaling. We identified serine residue 870 (S870) in metabotropic glutamate receptor 5 (mGluR5) as a direct substrate for protein kinase A (PKA). The phosphorylation of this site regulates the ability of mGluR5 to induce extracellular signal-regulated kinase (ERK) phosphorylation and intracellular Ca(2+) oscillations. This study provides a direct molecular mechanism by which PKA signaling interacts with glutamate neurotransmission.
authors: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York, USA; Department of Pharmacology, Kurume University School of Medicine, Kurume, Fukuoka, Japan; Department of Psychiatry, Kurume University School of Medicine, Kurume, Fukuoka, Japan; Cognitive and Molecular Research Institute of Brain Diseases, Kurume University, Kurume, Fukuoka, Japan.
authors: Ken
authors: K
authors: Uematsu
authors: Myriam
authors: M
authors: Heiman
authors: Marina
authors: M
authors: Zelenina
authors: Júlio
authors: J
authors: Padovan
authors: Brian T
authors: BT
authors: Chait
authors: Anita
authors: A
authors: Aperia
authors: Akinori
authors: A
authors: Nishi
authors: Paul
authors: P
authors: Greengard
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009924:Organ Culture Techniques; D010766:Phosphorylation / Q000502:physiology; D064529:Receptor, Metabotropic Glutamate 5 / Q000502:physiology*
chemical_list: D064529:Receptor, Metabotropic Glutamate 5; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: Ca2+ oscillations; extracellular signal-regulated kinase; mGluR5; phosphorylation; protein kinase A
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