title: Lysophosphatidic acid-induced neurite retraction in PC12 cells: control by phosphoinositide-Ca2+ signaling and Rho.
abstract: The endogenous phospholipid mediator lysophosphatidic acid (LPA) caused growth cone collapse, neurite retraction, and cell flattening in differentiated PC12 cells. Neurite retraction was blocked by cytochalasin B and ADP-ribosylation of the small-molecular-weight G protein Rho by the Clostridium botulinum C-3 toxin. LPA induced a transient rise in the level of inositol 1,4,5-trisphosphate, and retraction was blocked by inhibitors of phospholipase beta. Repeated application of LPA elicited homologous desensitization of the Ca2+ mobilization response. The activation of the phosphoinositide (PIP)-Ca2+ second messenger system played a permissive role in the morphoregulatory response. Blockers of protein kinase C--chelerythrine, a myristoylated pseudosubstrate peptide, staurosporine, and depletion of protein kinase C from the cells by long-term phorbol ester treatment--all diminished neurite retraction by interfering with LPA-induced Ca2+ mobilization, which was required for the withdrawal of neurites. A brief 15-min treatment with 4 beta-phorbol 12-myristate 13-acetate also blocked retraction and Ca2+ mobilization, by inactivating the LPA receptor. Inhibition of protein tyrosine phosphorylation by herbimycin diminished retraction. Although activation of the PIP-Ca2+ second messenger system appears necessary for the Rho-mediated rearrangements of the actin cytoskeleton, bradykinin, which activates similar signaling events, failed to cause retraction, indicating that a yet unidentified novel mechanism is also involved in the LPA-induced morphoregulatory 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: C
authors.initials: C
authors.lastname: Yang
authors.forename: D L
authors.initials: DL
authors.lastname: Dyer
authors.forename: R
authors.initials: R
authors.lastname: Miledi
mesh_terms: D000199:Actins / Q000502:physiology*; D000595:Amino Acid Sequence; D000818:Animals; D001905:Botulinum Toxins / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism / Q000502:physiology*; D003599:Cytoskeleton / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D019204:GTP-Binding Proteins / Q000502:physiology*; D008246:Lysophospholipids / Q000494:pharmacology*; D008969:Molecular Sequence Data; D016501:Neurites / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D016716:PC12 Cells; D010716:Phosphatidylinositols / Q000502:physiology*; D011065:Poly(ADP-ribose) Polymerases / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D015290:Second Messenger Systems; D015398:Signal Transduction
chemical_list: D000199:Actins; D008246:Lysophospholipids; D010716:Phosphatidylinositols; D011065:Poly(ADP-ribose) Polymerases; D011493:Protein Kinase C; D001905:Botulinum Toxins; D019204:GTP-Binding Proteins; D002118:Calcium