Fig. 1. Cellular organization of embryonic enteric nervous system and proposed signal transduction cascades regulating neuronal motility. (A) Schematic drawing of locust embryonic foregut and anterior midgut at 65% E in dorsal view. Midgut is shaded light gray, enteric ganglia and neurons are dark gray. Two of the four migratory pathways are visible on the dorsal midgut. Already developing foregut plexus is omitted for sake of clarity. Double-headed arrow indicates measured distance of enteric neuron migration after 24 hours in vivo culture incubation. ca, cecum; en, enteric neuron; env, esophageal nerve; fc, frontal connective; fg, frontal ganglion; hg, hypocerebral ganglion; ig, ingluvial ganglion; rnv, recurrent nerve. Anterior is towards the left as in following figures. (B) Schematic diagram of CO and NO/cGMP signaling transduction influencing enteric neuron migration. Ca²⁺-calmodulin (CaM)-activated NOS catalyses the conversion of L-arginine into L-citrulline, thereby releasing NO. NOS activity can be stimulated by applying an excess of arginine or blocked by the inhibitor 7-NI. The diffusible NO binds to the heme moiety in soluble guanylyl cyclase (sGC), thus stimulating synthesis of cGMP. Intercellular diffusing NO can be trapped by the extracellularly acting scavenger hemoglobin. The stimulation of sGC with YC-1 artificially amplifies cGMP production. Heme oxygenase enzymes (HO), such as the HO-2-immunoreactive constitutive isoform, release CO as a by-product during heme degradation. The enzyme activity can be manipulated by its substrate analog hemin or metalloporphyrin inhibitors such as ZnBG and ZnPP-IX. CORM-II is an exogenous CO donor. CO competes with NO for binding to sGC (blunt tip), leading only to a rather modest increase in the cGMP level.