Fig. 10.

Illustration of the molecular pathways involved in glutamate homeostasis and signaling through metabotropic glutamate receptors (mGluRs). The upper panel (A) depicts the synaptic interaction between presynaptic and postsynaptic neurons, highlighting the roles of glutaminase, glutamine synthetase, VGLUT, and EAAT1/2 in glutamate cycling and mGluR-mediated signaling. Group I mGluRs (mGluR1 and mGluR5) activate G_q proteins, leading to the release of intracellular Ca²⁺ and activation of protein kinase C (PKC). Group II mGluRs (mGluR2 and mGluR3) couple to G_i/o proteins, which inhibit adenylate cyclase, reducing cAMP levels and protein kinase A (PKA) activity, thus protecting neurons from excitotoxicity. Group III mGluRs (mGluR4, mGluR6, mGluR7, and mGluR8) also couple to G_i/o proteins, further inhibiting glutamate release. The lower panel (B) outlines the intracellular signaling cascades triggered by the activation of these mGluRs, detailing the involvement of key molecules such as PLCβ, PKC, PKA, and GSK3β, which are critical for synaptic plasticity and memory functions. Early melatonin intervention modulates these pathways, reducing glutamate toxicity and ameliorating cognitive deficits in AD models. This picture was created by Bio Render