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Lysophosphatidic Acid‐Induced Neurite Retraction in PC12 Cells: Control by Phosphoinositide‐Ca 2+ Signaling and Rho
Author(s) -
Tigyi Gabor,
Fischer David J.,
Sebök Ágnes,
Yang Charles,
Dyer David L.,
Miledi Ricardo
Publication year - 1996
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1996.66020537.x
Subject(s) - lysophosphatidic acid , second messenger system , neurite , microbiology and biotechnology , wortmannin , protein kinase c , biology , g protein , signal transduction , cytochalasin d , phosphatidylinositol , biochemistry , cytoskeleton , receptor , in vitro , cell
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 β. Repeated application of LPA elicited homologous desensitization of the Ca 2+ mobilization response. The activation of the phosphoinositide (PIP)‐Ca 2+ 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 Ca 2+ mobilization, which was required for the withdrawal of neurites. A brief 15‐min treatment with 4β‐phorbol 12‐myristate 13‐acetate also blocked retraction and Ca 2+ mobilization, by inactivating the LPA receptor. Inhibition of protein tyrosine phosphorylation by herbimycin diminished retraction. Although activation of the PIP‐Ca 2+ 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.