Document Detail

The G alpha(o/i)-coupled cannabinoid receptor-mediated neurite outgrowth involves Rap regulation of Src and Stat3.
MedLine Citation:
PMID:  16046413     Owner:  NLM     Status:  MEDLINE    
The study of the signaling pathways regulating neurite outgrowth in culture is important because of their potential role in neuronal differentiation in vivo. We have previously shown that the G alpha(o/i)-coupled CB1 cannabinoid receptor (CB1R) activates Rap1 to induce neurite outgrowth. G alpha(o/i) also activates the Src-Stat3 pathway. Here, we studied the relationship between the G alpha(o/i)-Rap1 and Src-Stat3 pathways and the role of these signaling pathways in CB1R-mediated neurite outgrowth in Neuro-2A cells. The CB1 agonist HU-210 induced pertussis toxin-sensitive Src and Stat3 phosphorylation. Dominant negative (DN) mutants of Src and Stat3 blocked CB1R-induced neurite outgrowth. Constitutively active Rap 1B and Ral-activated Src and CB1R-induced Src phosphorylation was inhibited by Rap1-DN and Ral-DN, indicating that both Rap1 and Ral mediate downstream signaling from G alpha(o/i) for Src activation. Rap1-activated Ral and Ral-DN blocked Rap-induced Src phosphorylation. G alpha(o)-induced Stat3 activation was blocked by Ral-DN, whereas v-Src-induced Stat3 activation was not inhibited by Ral-DN, indicating that the CB1R, through G alpha(o), mediates the sequential activation of Rap1 to Ral to Src to Stat3 in Neuro-2A cells. Downstream of Src, the CB1R also activated Rac1 and JNK, which enhanced CBR1-mediated Stat3 activation. Rac-DN blocked CB1R-induced activation of JNK. Pharmacological inhibition of JNK blocked Src and CB1R activation of Stat3, indicating that Rac and JNK are also involved in CB1R-mediated neurite outgrowth. Overall, this study demonstrated that G alpha(o/i)-coupled CB1R triggers neurite outgrowth in Neuro-2A through the activation of a signaling network containing two pathways that bifurcate at Src and converge at Stat3.
John Cijiang He; Ivone Gomes; Tracy Nguyen; Gomathi Jayaram; Prahlad T Ram; Lakshmi A Devi; Ravi Iyengar
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, P.H.S.     Date:  2005-07-26
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  280     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2005 Sep 
Date Detail:
Created Date:  2005-09-26     Completed Date:  2005-11-30     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  33426-34     Citation Subset:  IM    
Department of Pharmacology, Mount Sinai School of Medicine, New York, New York 10029, USA.
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MeSH Terms
Catalytic Domain
Cell Line, Tumor
GTP-Binding Protein alpha Subunits, Gi-Go / physiology*
Gene Expression Regulation, Neoplastic
Green Fluorescent Proteins / chemistry,  metabolism
JNK Mitogen-Activated Protein Kinases / metabolism
Models, Biological
Neurites / physiology*
Receptor, Cannabinoid, CB1 / metabolism*
Signal Transduction
Tetrahydrocannabinol / analogs & derivatives,  pharmacology
rap1 GTP-Binding Proteins / physiology*
src-Family Kinases / genetics,  metabolism*
Grant Support
Reg. No./Substance:
0/Receptor, Cannabinoid, CB1; 112924-45-5/HU 211; 147336-22-9/Green Fluorescent Proteins; 1972-08-3/Tetrahydrocannabinol; EC Kinases; EC Mitogen-Activated Protein Kinases; EC Protein alpha Subunits, Gi-Go; EC GTP-Binding Proteins

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