Fig. 7.

Model for architecture of cGMP signaling in PQR. In our model, an [O₂] increase persistently activates prenylated GCY-35/GCY-36 atypical soluble guanylate cyclases located at the membrane. The resulting increase in [cGMP] gates cGMP channels, promoting Na⁺ and Ca²⁺ entry. The rise in [cGMP] and [Ca²⁺] stimulates competing negative feedback loops that sculpt signaling dynamics. In one loop, increasing [cGMP] stimulates EGL-4 PKG and activates PDE-2. By destroying cGMP, PKG–PDE-2 negative feedback acts as a smoothing filter, keeping in check CNGC gating. This control mechanism limits Ca²⁺-dependent negative feedbacks on cGMP that are mediated by PDE-1 and PDE-1-independent mechanisms. Depolarization caused by sustained gating of CNGC activates L-type voltage-gated Ca²⁺ channels and leads to Ca²⁺ release from intracellular stores via ryanodine and IP₃ receptors, and sustained signaling. A fall in O₂ results in decreased production of cGMP, rapid cGMP breakdown by activated PDE-1 and PDE-2, closure of cGMP channels, and termination of signaling. Note that this speculative model likely omits additional regulatory control.