LYSOPHOSPHATIDIC ACID-INDUCED NEURITE RETRACTION IN PC12 CELLS - NEURITE-PROTECTIVE EFFECTS OF CYCLIC-AMP SIGNALING

Effects of the cyclic AMP second messenger system were studied on the retraction of neurites elicited by the phospholipid mediator lysophosp hatidic acid (LPA) in PC12 cells. LPA stimulation inhibited adenylyl c yclase, indicating that the LPA receptor couples to the heterotrimeric G(i) proteins, However, pertussis toxin or expression of dominant neg ative Ras did not prevent neurite retraction. In contrast, cholera tox in, forskolin, and application of dibutyryl-cyclic AMP prevented neuri te retraction. The neurite-protective effect of forskolin was blocked by Rp-adenosine 3',5'-phosphorothioate. Forskolin and dibutyryl-cyclic AMP both failed to protect neurites in A126-1B2 and 123.7 cells, whic h lack cyclic AMP-activated protein kinase. Data indicate that elevati on of cyclic AMP levels triggers a cyclic AMP-activated protein kinase -dependent mechanism that opposes the functioning of the morphoregulat ory signaling activated by LPA, ADP-ribosylation of Rho by the Clostri dium botulinum C-3 toxin in 123.7 cells caused neuronal differentiatio n, indicated by neurite extension, and blocked LPA-induced neurite ret raction, LPA activates G(q)- and G(i)-linked signaling in parallel; th erefore, a morphoregulatory signaling network hypothesis is proposed v ersus the simplistic approach of a signaling pathway. The signaling ne twork integrates the receptor-activated individual, sequential, and pa rallel signaling events into an interactive network whose individual c omponents may fulfill required and permissive functions encoding the c ellular response.