title: Lysophosphatidic acid-induced neurite retraction in PC12 cells: neurite-protective effects of cyclic AMP signaling.
abstract: Effects of the cyclic AMP second messenger system were studied on the retraction of neurites elicited by the phospholipid mediator lysophosphatidic acid (LPA) in PC12 cells. LPA stimulation inhibited adenylyl cyclase, indicating that the LPA receptor couples to the heterotrimeric Gi proteins. However, pertussis toxin or expression of dominant negative Ras did not prevent neurite retraction. In contrast, cholera toxin, forskolin, and application of dibutyryl-cyclic AMP prevented neurite 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, which lack cyclic AMP-activated protein kinase. Data indicate that elevation of cyclic AMP levels triggers a cyclic AMP-activated protein kinase-dependent mechanism that opposes the functioning of the morphoregulatory signaling activated by LPA. ADP-ribosylation of Rho by the Clostridium botulinum C-3 toxin in 123.7 cells caused neuronal differentiation, indicated by neurite extension, and blocked LPA-induced neurite retraction. LPA activates Gq- and Gi-linked signaling in parallel; therefore, a morphoregulatory signaling network hypothesis is proposed versus the simplistic approach of a signaling pathway. The signaling network integrates the receptor-activated individual, sequential, and parallel signaling events into an interactive network whose individual components may fulfill required and permissive functions encoding the cellular response.
authors.affiliation: Department of Physiology and Biophysics, University of Tennessee at Memphis 38163, USA.
authors.forename: G
authors.initials: G
authors.lastname: Tigyi
authors.forename: D J
authors.initials: DJ
authors.lastname: Fischer
authors.forename: A
authors.initials: A
authors.lastname: Sebök
authors.forename: F
authors.initials: F
authors.lastname: Marshall
authors.forename: D L
authors.initials: DL
authors.lastname: Dyer
authors.forename: R
authors.initials: R
authors.lastname: Miledi
mesh_terms: D036002:ADP Ribose Transferases / Q000494:pharmacology; D000818:Animals; D001905:Botulinum Toxins; D002118:Calcium / Q000502:physiology; D002455:Cell Division; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000502:physiology; D007527:Isoenzymes / Q000378:metabolism; D008246:Lysophospholipids / Q000494:pharmacology*; D016501:Neurites / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D016716:PC12 Cells; D051381:Rats; D015398:Signal Transduction; D013873:Thionucleotides / Q000494:pharmacology
chemical_list: D007527:Isoenzymes; D008246:Lysophospholipids; D013873:Thionucleotides; C016957:adenosine-3',5'-cyclic phosphorothioate; D000242:Cyclic AMP; D036002:ADP Ribose Transferases; C063007:exoenzyme C3, Clostridium botulinum; D017868:Cyclic AMP-Dependent Protein Kinases; D001905:Botulinum Toxins; D019204:GTP-Binding Proteins; D002118:Calcium