The proposed pathway by which sialorphin causes smooth muscle relaxation and thereby improves erectile function. CNP binds to its membrane receptor on corporal smooth muscle cells and activates GC-B. The CNP is degraded by NEP. However, in the presence of sialorphin (acting as a NEP inhibitor), the CNP has a prolonged effect, activating downstream mechanisms resulting in smooth muscle relaxation, mediated by the secondary messenger cGMP. Among these downstream activators are maxi-K channels. Efflux of potassium from the cells causes hyperpolarization of the smooth muscle cell membrane, inhibiting influx of Ca2+ through calcium channels. Lowered intracellular calcium causes inactivation myosin light-chain kinase (MLCK), thereby promoting smooth muscle relaxation. GTP, guanosine triphosphate, PKA, protein kinase A, PKC, protein kinase C; PKG, protein kinase G, MLC20, myosin light chain.