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

Uematsu K, Heiman M, Zelenina M, Padovan J, Chait BT, Aperia A, Nishi A, Greengard P

J. Neurochem. 132 (6) 677-686 [2015-03-00; online 2015-03-04]

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.

Affiliated researcher

PubMed 25639954

DOI 10.1111/jnc.13038

Crossref 10.1111/jnc.13038

pmc: PMC4359654
mid: NIHMS665071


Publications 7.1.2