Protein kinase A directly phosphorylates metabotropic glutamate receptor 5 to modulate its function
Author(s)Uematsu, Ken; Heiman, Myriam; Zelenina, Marina; Padovan, Julio; Chait, Brian T.; Aperia, Anita; Nishi, Akinori; Greengard, Paul; ... Show more Show less
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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[superscript 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[superscript 2+] oscillations. This study provides a direct molecular mechanism by which PKA signaling interacts with glutamate neurotransmission.
DepartmentMassachusetts Institute of Technology. Department of Brain and Cognitive Sciences; Picower Institute for Learning and Memory
Journal of Neurochemistry
Uematsu, Ken, Myriam Heiman, Marina Zelenina, Julio Padovan, Brian T. Chait, Anita Aperia, Akinori Nishi, and Paul Greengard. “Protein Kinase A Directly Phosphorylates Metabotropic Glutamate Receptor 5 to Modulate Its Function.” Journal of Neurochemistry 132, no. 6 (March 2015): 677–686.
Author's final manuscript