The Journal of Neuroscience, December 15, 1999, 19(24):10843-10855
Thrombin-Induced Growth Cone Collapse: Involvement of
Phospholipase A2 and Eicosanoid Generation
Becky A.
de la Houssaye,
Keith
Mikule,
Dejan
Nikolic, and
Karl
H.
Pfenninger
Department of Cellular and Structural Biology, University of
Colorado School of Medicine and University of Colorado Cancer Center,
Denver, Colorado 80262
The studies presented here explore intracellular signals resulting
from the action of repellents on growth cones. Growth cone challenge
with thrombin or thrombin receptor-activating peptide (TRAP) triggers
collapse via a receptor-mediated process. The results indicate that
this involves activation of cytosolic phospholipase A2
(PLA2) and eicosanoid synthesis. The collapse
response to repellents targets at least two functional units of the
growth cone, the actin cytoskeleton and substratum adhesion sites. We
show in a cell-free assay that thrombin and TRAP cause the detachment
of isolated growth cones from laminin. Biochemical analyses of isolated growth cones reveal that thrombin and TRAP stimulate cytosolic PLA2 but not phospholipase C. In addition, thrombin
stimulates synthesis of 12- and 15-hydroxyeicosatetraenoic acid (HETE)
from the released arachidonic acid via a lipoxygenase (LO) pathway. A
selective LO inhibitor blocks 12/15-HETE synthesis in growth cones and
inhibits thrombin-induced growth cone collapse. Exogenously applied
12(S)-HETE mimics the thrombin effect and induces growth cone collapse in culture. These observations indicate that
thrombin-induced growth cone collapse occurs by a mechanism that
involves the activation of cytosolic PLA2 and the
generation of 12/15-HETE.
Key words:
growth cone; collapse; thrombin; signaling; phospholipase
A2; lipoxygenase
Copyright © 1999 Society for Neuroscience 0270-6474/99/192410843-13$05.00/0
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