Tags

Type your tag names separated by a space and hit enter

Cannabinoid CB1 receptors transactivate multiple receptor tyrosine kinases and regulate serine/threonine kinases to activate ERK in neuronal cells.
Br J Pharmacol. 2012 Apr; 165(8):2497-511.BJ

Abstract

BACKGROUND AND PURPOSE

Signalling networks that regulate the progression of cannabinoid CB(1) receptor-mediated extracellular signal-regulated kinase (ERK) activation in neurons are poorly understood. We investigated the cellular mechanisms involved in CB(1) receptor-stimulated ERK phosphorylation in a neuronal cell model.

EXPERIMENTAL APPROACH

Murine N18TG2 neuronal cells were used to analyse the effect of specific protein kinase and phosphatase inhibitors on CB(1) receptor-stimulated ERK phosphorylation. The LI-COR In Cell Western assay and immunoblotting were used to measure ERK phosphorylation.

KEY RESULTS

The time-course of CB(1) receptor-stimulated ERK activation occurs in three phases that are regulated by distinct cellular mechanisms in N18TG2 cells. Phase I (0-5 min) maximal ERK phosphorylation is mediated by CB(1) receptor-stimulated ligand-independent transactivation of multiple receptor tyrosine kinases (RTKs). Phase I requires G(i/o) βγ subunit-stimulated phosphatidylinositol 3-kinase activation and Src kinase activation and is modulated by inhibition of cAMP-activated protein kinase A (PKA) levels. Src kinase activation is regulated by the protein tyrosine phosphatases 1B and Shp1. The Phase II (5-10 min) rapid decline in ERK phosphorylation involves PKA inhibition and serine/threonine phosphatase PP1/PP2A activation. The Phase III (>10 min) plateau in ERK phosphorylation is mediated by CB(1) receptor-stimulated, ligand-independent, transactivation of multiple RTKs.

CONCLUSIONS AND IMPLICATIONS

The complex expression of CB(1) receptor-stimulated ERK activation provides cellular selectivity, modulation of sensitivity to agonists, and coincidence detection with RTK signalling. RTK and PKA pathways may provide routes to novel CB(1) -based therapeutic interventions in the treatment of addictive disorders or neurodegenerative diseases. LINKED ARTICLES This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7.

Links

PMC Free PDF
PMC Free Full Text
Aggregator Full Text

Authors+Show Affiliations

Dalton GD
Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
Howlett AC
No affiliation info available

MeSH

AnimalsBenzoxazinesCannabinoidsCell Line, TumorMiceMorpholinesNaphthalenesNeuronsPhosphorylationProtein KinasesReceptor, Cannabinoid, CB1Transcriptional Activation

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21518335

Citation

Dalton, George D., and Allyn C. Howlett. "Cannabinoid CB1 Receptors Transactivate Multiple Receptor Tyrosine Kinases and Regulate Serine/threonine Kinases to Activate ERK in Neuronal Cells." British Journal of Pharmacology, vol. 165, no. 8, 2012, pp. 2497-511.
Dalton GD, Howlett AC. Cannabinoid CB1 receptors transactivate multiple receptor tyrosine kinases and regulate serine/threonine kinases to activate ERK in neuronal cells. Br J Pharmacol. 2012;165(8):2497-511.
Dalton, G. D., & Howlett, A. C. (2012). Cannabinoid CB1 receptors transactivate multiple receptor tyrosine kinases and regulate serine/threonine kinases to activate ERK in neuronal cells. British Journal of Pharmacology, 165(8), 2497-511. https://doi.org/10.1111/j.1476-5381.2011.01455.x
Dalton GD, Howlett AC. Cannabinoid CB1 Receptors Transactivate Multiple Receptor Tyrosine Kinases and Regulate Serine/threonine Kinases to Activate ERK in Neuronal Cells. Br J Pharmacol. 2012;165(8):2497-511. PubMed PMID: 21518335.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cannabinoid CB1 receptors transactivate multiple receptor tyrosine kinases and regulate serine/threonine kinases to activate ERK in neuronal cells. AU - Dalton,George D, AU - Howlett,Allyn C, PY - 2011/4/27/entrez PY - 2011/4/27/pubmed PY - 2012/7/28/medline SP - 2497 EP - 511 JF - British journal of pharmacology JO - Br J Pharmacol VL - 165 IS - 8 N2 - BACKGROUND AND PURPOSE: Signalling networks that regulate the progression of cannabinoid CB(1) receptor-mediated extracellular signal-regulated kinase (ERK) activation in neurons are poorly understood. We investigated the cellular mechanisms involved in CB(1) receptor-stimulated ERK phosphorylation in a neuronal cell model. EXPERIMENTAL APPROACH: Murine N18TG2 neuronal cells were used to analyse the effect of specific protein kinase and phosphatase inhibitors on CB(1) receptor-stimulated ERK phosphorylation. The LI-COR In Cell Western assay and immunoblotting were used to measure ERK phosphorylation. KEY RESULTS: The time-course of CB(1) receptor-stimulated ERK activation occurs in three phases that are regulated by distinct cellular mechanisms in N18TG2 cells. Phase I (0-5 min) maximal ERK phosphorylation is mediated by CB(1) receptor-stimulated ligand-independent transactivation of multiple receptor tyrosine kinases (RTKs). Phase I requires G(i/o) βγ subunit-stimulated phosphatidylinositol 3-kinase activation and Src kinase activation and is modulated by inhibition of cAMP-activated protein kinase A (PKA) levels. Src kinase activation is regulated by the protein tyrosine phosphatases 1B and Shp1. The Phase II (5-10 min) rapid decline in ERK phosphorylation involves PKA inhibition and serine/threonine phosphatase PP1/PP2A activation. The Phase III (>10 min) plateau in ERK phosphorylation is mediated by CB(1) receptor-stimulated, ligand-independent, transactivation of multiple RTKs. CONCLUSIONS AND IMPLICATIONS: The complex expression of CB(1) receptor-stimulated ERK activation provides cellular selectivity, modulation of sensitivity to agonists, and coincidence detection with RTK signalling. RTK and PKA pathways may provide routes to novel CB(1) -based therapeutic interventions in the treatment of addictive disorders or neurodegenerative diseases. LINKED ARTICLES This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7. SN - 1476-5381 UR - https://www.unboundmedicine.com/medline/citation/21518335/Cannabinoid_CB1_receptors_transactivate_multiple_receptor_tyrosine_kinases_and_regulate_serine/threonine_kinases_to_activate_ERK_in_neuronal_cells_ L2 - https://doi.org/10.1111/j.1476-5381.2011.01455.x DB - PRIME DP - Unbound Medicine ER -