1. Schematic of mGluRI-NMDAR signaling chains: Homer-mediated (white element titles) and G-protein-mediated (black element titles).
Schematic of mGluRI-NMDAR signaling chains: Homer-mediated (white element titles) and G-protein-mediated (black element titles). Red lightning bolts indicate specific points where G-protein- and Homer-mediated chain were interrupted by PeTX and Homer1a, respectively. mGluRIs and NMDARs are physically connected by scaffolding proteins of postsynaptic density, which transmit modulatory signal through scaffolding proteins in the following order: mGluRI → preso1 → Homer → SH3 and multiple ankyrin repeat domains (Shank) → guanylate-kinase-associated protein (GKAP) → postsynaptic density 95 (PSD-95) → NMDAR. Glutamate-containing vesicles of presynaptic bouton, being exocytosed, release glutamate into synaptic cleft. Glutamate binding to mGluRI and glutamate + glycine binding to NMDAR activate both receptors. Phosphorylated NMDAR allows influx of extracellular calcium (ECCa2+) into cell; this triggers release of intracellular calcium (ICCa2+) from ER. Activation (phosphorylation) of mGluRI, induced by glutamate binding, triggers activation of the G-protein Gq, subsequently activating phospholipase C (PLC). PLC initiates conversion of phosphoinositide (PI) to inositol 1,4,5-triphosphate (IP3) and subsequent activation of diacylglycerol (DAG); IP3 initiates release of intracellular Ca2+. DAG, being combined with increased Ca2+ concentration due to NMDAR activation, causes phosphorylation of protein kinase C (PKC). PKC initiates phosphorylation of proline-rich tyrosine kinase/cell adhesion kinase β (Pyk2/CAKβ), and subsequently the cellular tyrosine kinase protein (Src). In turn, SRC potentiates NMDAR. Negative feedback loop occurs after Ca2+ influxed through NMDARs activates Ca2+-dependent protein phosphatase 2B/calcineurin (PP2B/CaN), which dephosphorylates (i.e., at least partially deactivates) mGluRIs (Matosin and Newell, 2013).
Nathanael O'Neill et al. J. Neurosci. 2018;38:
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