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. doi: 10.1111/j.1476-5381.2011.01455.x.


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 To view Part I of Cannabinoids in Biology and Medicine visit

Publication types

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

MeSH terms

  • Animals
  • Benzoxazines / pharmacology
  • Cannabinoids / pharmacology
  • Cell Line, Tumor
  • Mice
  • Morpholines / pharmacology
  • Naphthalenes / pharmacology
  • Neurons / metabolism*
  • Phosphorylation
  • Protein Kinases / metabolism*
  • Receptor, Cannabinoid, CB1 / metabolism*
  • Transcriptional Activation


  • Benzoxazines
  • Cannabinoids
  • Morpholines
  • Naphthalenes
  • Receptor, Cannabinoid, CB1
  • (3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
  • Protein Kinases