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Distinct regulation of bioenergetics and translation by group I mGluR and NMDAR
Author(s) -
Ghosh Dastidar Sudhriti,
Das Sharma Shreya,
Chakraborty Sumita,
Chattarji Sumantra,
Bhattacharya Aditi,
Muddashetty Ravi S
Publication year - 2020
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201948037
Subject(s) - metabotropic glutamate receptor , bioenergetics , glutamate receptor , phosphorylation , biology , microbiology and biotechnology , ampk , nmda receptor , receptor , biochemistry , chemistry , neuroscience , protein kinase a , mitochondrion
Neuronal activity is responsible for the high energy consumption in the brain. However, the cellular mechanisms draining ATP upon the arrival of a stimulus are yet to be explored systematically at the post‐synapse. Here, we provide evidence that a significant fraction of ATP is consumed upon glutamate stimulation to energize mGluR‐induced protein synthesis. We find that both mGluR and NMDAR alter protein synthesis and ATP consumption with distinct kinetics at the synaptic‐dendritic compartments. While mGluR activation leads to a rapid and sustained reduction in neuronal ATP levels, NMDAR activation has no immediate impact on the same. ATP consumption correlates inversely with the kinetics of protein synthesis for both receptors. We observe a persistent elevation in protein synthesis within 5 minutes of mGluR activation and a robust inhibition of the same within 2 minutes of NMDAR activation, assessed by the phosphorylation status of eEF2 and metabolic labeling. However, a delayed protein synthesis‐dependent ATP expenditure ensues after 15 minutes of NMDAR stimulation. We identify a central role for AMPK in the correlation between protein synthesis and ATP consumption. AMPK is dephosphorylated and inhibited upon mGluR activation, while it is phosphorylated upon NMDAR activation. Perturbing AMPK activity disrupts receptor‐specific modulations of eEF2 phosphorylation and protein synthesis. Our observations, therefore, demonstrate that the regulation of the AMPK‐eEF2 signaling axis by glutamate receptors alters neuronal protein synthesis and bioenergetics.