Lysophosphatidic acid-induced neurite retraction in PC12 cells: control by phosphoinositide-Ca2+ signaling and Rho

J Neurochem. 1996 Feb;66(2):537-48. doi: 10.1046/j.1471-4159.1996.66020537.x.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Actins / physiology*
  • Amino Acid Sequence
  • Animals
  • Botulinum Toxins / pharmacology
  • Calcium / metabolism
  • Calcium / physiology*
  • Cytoskeleton / drug effects
  • Cytoskeleton / physiology
  • Dose-Response Relationship, Drug
  • Enzyme Activation
  • GTP-Binding Proteins / physiology*
  • Lysophospholipids / pharmacology*
  • Molecular Sequence Data
  • Neurites / drug effects*
  • Neurites / physiology
  • Neurons / cytology
  • Neurons / drug effects*
  • Neurons / physiology
  • PC12 Cells
  • Phosphatidylinositols / physiology*
  • Poly(ADP-ribose) Polymerases / pharmacology
  • Protein Kinase C / metabolism
  • Rats
  • Second Messenger Systems
  • Signal Transduction*


  • Actins
  • Lysophospholipids
  • Phosphatidylinositols
  • Poly(ADP-ribose) Polymerases
  • Protein Kinase C
  • Botulinum Toxins
  • GTP-Binding Proteins
  • Calcium