Hypothetical model of H₂O₂ sensing and signaling in <i>C</i>. <i>elegans</i> I2 and PHA neurons based on this and on previous work.

(A-B) Hypothetical model of H2O2-induced neuronal activation, based on our data and on previous studies. Schematic drawing of a presynaptic button in I2 (A) and PHA (B) neurons, illustrating the presumptive H2O2-PRDX-2-mediated neuronal activation in both cases (modelled in S12 Fig). High doses of H2O2 (1mM) are sensed by both neurons, but only PHA neurons respond to 10μM H2O2, as illustrated in red. In this model, H2O2 would freely diffuse through the neuron plasma membrane and oxidize PRDX-2, presumably leading to LITE-1 or GUR-3 activation. Receptor activation is likely relayed by cGMP signaling, resulting in the opening of voltage-gated calcium channels (in grey) and neurotransmitter release (glutamate in both cases), triggering an adapted response. In PHA neurons, the PMK-1/p38MAPK pathway is additionally required to promote neuronal response to micromolar doses of H2O2, potentially through OSM-9 phosphorylation, as observed in ASH neurons [3]. See Discussion for further details and bibliographic references.