Figure 8. Model of H₂O₂‐induced modulation of presynaptic activity in spinal VH neurons .

A, H₂O₂ stimulates glutamate release by Ca²⁺ influx via N‐type VGCC (i) and Ca²⁺ release from the ER via RyR (ii) and IP₃R (iii). Oxidation of RyR cysteine residues increases RyR sensitivity to Ca²⁺, resulting in excessive activation of RyR‐mediated CICR. The effects of H₂O₂ on IP₃R‐related signalling are downstream of PLC‐β. B, H₂O₂ increases GABAergic transmission by stimulating Ca²⁺ release from the ER via IP₃R; its site of action is downstream of PLC‐β (i). Moreover, diffusion of GABA away from the release site activates presynaptic GABA_A and to a lesser degree GABA_B receptors (ii), thereby inhibiting glutamate release from excitatory presynaptic terminals. These effects by GABA may protect postsynaptic neurons from excitotoxicity resulting from excessive glutamate. Mito, mitochondria; CaN, calcineurin; PIP₂, phosphatidylinositol 4,5‐bisphosphate; DAG, diacylglycerol.