Figure 3. Potential mechanisms of VGLUT2-mediated protection from neurotoxicity.

(A) VGLUT2 enhances DA loading into synaptic vesicles via VMAT2 by increasing the vesicular pH gradient (ΔpH)⁵⁰. This decreases cytoplasmic DA levels, making less free DA available to generate neurotoxic ROS that damage mitochondria. (B) VGLUT2-mediated glutamate sequestration lowers cytoplasmic glutamate to diminish glutamatergic excitotoxicity. VGLUT2-expressing DA neurons also express EAAT3, which removes glutamate from the extracellular space, preventing glutamate-mediated excitotoxicity. (C) Glutamate can be converted to α-ketoglutarate (α-KG) to feed into the TCA cycle and maintain mitochondrial ATP production. Glutamate also replenishes glutathione to reduce ROS accumulation and protect DA neurons.