Protein kinase A directly phosphorylates metabotropic glutamate receptor 5 to modulate its function

• Published in: Journal of neurochemistry 2015-03, Vol.132 (6), p.677-686
• Main Authors: Uematsu, Ken, Heiman, Myriam, Zelenina, Marina, Padovan, Júlio, Chait, Brian T., Aperia, Anita, Nishi, Akinori, Greengard, Paul
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Binding Sites - physiology; Ca2+ oscillations; Cyclic AMP-Dependent Protein Kinases - genetics; Cyclic AMP-Dependent Protein Kinases - metabolism; extracellular signal‐regulated kinase; HEK293 Cells; Humans; Kinases; mGluR5; Mice; Mice, Inbred C57BL; Mice, Knockout; Organ Culture Techniques; Phosphorylation; Phosphorylation - physiology; protein kinase A; Proteins; Receptor, Metabotropic Glutamate 5 - physiology
• ISSN: 0022-3042; 1471-4159; 1471-4159
• DOI: 10.1111/jnc.13038

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 Ca2+ 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 Ca2+ oscillations. This study provides a direct molecular mechanism by which PKA signaling interacts with glutamate neurotransmission. 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 Ca2+ oscillations. This study provides a direct molecular mechanism by which PKA signaling interacts with glutamate neurotransmission.