| The G alpha(o/i)-coupled cannabinoid receptor-mediated neurite outgrowth involves Rap regulation of Src and Stat3. | |
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MedLine Citation:
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PMID: 16046413 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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John Cijiang He; Ivone Gomes; Tracy Nguyen; Gomathi Jayaram; Prahlad T Ram; Lakshmi A Devi; Ravi Iyengar |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, P.H.S. Date: 2005-07-26 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 280 ISSN: 0021-9258 ISO Abbreviation: J. Biol. Chem. Publication Date: 2005 Sep |
Date Detail:
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Created Date: 2005-09-26 Completed Date: 2005-11-30 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 33426-34 Citation Subset: IM |
Affiliation:
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Department of Pharmacology, Mount Sinai School of Medicine, New York, New York 10029, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals 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 Mice Models, Biological Neurites / physiology* Phosphorylation Receptor, Cannabinoid, CB1 / metabolism* Signal Transduction Tetrahydrocannabinol / analogs & derivatives, pharmacology rap1 GTP-Binding Proteins / physiology* src-Family Kinases / genetics, metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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CA-81050/CA/NCI NIH HHS; DA-019521/DA/NIDA NIH HHS; DA-08863/DA/NIDA NIH HHS; DK-65495/DK/NIDDK NIH HHS; GM-54508/GM/NIGMS NIH HHS; HL-07824/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Receptor, Cannabinoid, CB1; 112924-45-5/HU 211; 147336-22-9/Green Fluorescent Proteins; 1972-08-3/Tetrahydrocannabinol; EC 2.7.10.2/src-Family Kinases; EC 2.7.11.24/JNK Mitogen-Activated Protein Kinases; EC 3.6.5.1/GTP-Binding Protein alpha Subunits, Gi-Go; EC 3.6.5.2/rap1 GTP-Binding Proteins |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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