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Lysophosphatidic Acid‐Induced Neurite Retraction in PC12 Cells: Neurite‐Protective Effects of Cyclic AMP Signaling
Author(s) -
Tigyi Gabor,
Fischer David J.,
Sebök Ágnes,
Marshall Frakeetta,
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.1471-4159.1996.66020549.x
Subject(s) - neurite , lysophosphatidic acid , forskolin , microbiology and biotechnology , adenylyl cyclase , cholera toxin , second messenger system , pertussis toxin , signal transduction , biology , gs alpha subunit , protein kinase a , heterotrimeric g protein , g protein , chemistry , endocrinology , phosphorylation , receptor , biochemistry , stimulation , in vitro
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 G i 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 G q ‐ and G i ‐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.