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Cannabinoid receptor-induced neurite outgrowth is mediated by Rap1 activation through G(alpha)o/i-triggered proteasomal degradation of Rap1GAPII.

The G(alpha)o/i-coupled CB1 cannabionoid receptor induces neurite outgrowth in Neuro-2A cells. The mechanisms of signaling through G(alpha)o/i to induce neurite outgrowth were studied. The expression of G(alpha)o/i reduces the stability of its direct interactor protein, Rap1GAPII, by targeting it for ubiquitination and proteasomal degradation. This results in the activation of Rap1. G(alpha)o/i-induced activation of endogenous Rap1 in Neuro-2A cells is blocked by the proteasomal inhibitor lactacystin. G(alpha)o/i stimulates neurite outgrowth that is blocked by the expression of dominant negative Rap1. Expression of Rap1GAPII also blocks the G(alpha)o/i-induced neurite outgrowth and treatment with proteasomal inhibitors potentiates this inhibition. The endogenous G(alpha)o/i-coupled cannabinoid (CB1) receptor in Neuro-2A cells stimulates the degradation of Rap1GAPII; activation of Rap1 and treatment with pertussis toxin or lactacystin blocks these effects. The CB1 receptor-stimulated neurite outgrowth is blocked by treatment with pertussis toxin, small interfering RNA for Rap, lactacystin, and expression of Rap1GAPII. Thus, the G(alpha)o/i-coupled cannabinoid receptor, by regulating the proteasomal degradation of Rap1GAPII, activates Rap1 to induce neurite outgrowth.

Pubmed ID: 15657046


  • Jordan JD
  • He JC
  • Eungdamrong NJ
  • Gomes I
  • Ali W
  • Nguyen T
  • Bivona TG
  • Philips MR
  • Devi LA
  • Iyengar R


The Journal of biological chemistry

Publication Data

March 25, 2005

Associated Grants

  • Agency: NIDA NIH HHS, Id: DA-00458
  • Agency: NIDA NIH HHS, Id: DA-05798
  • Agency: NIDA NIH HHS, Id: DA-08863
  • Agency: NIGMS NIH HHS, Id: GM-54508
  • Agency: NIGMS NIH HHS, Id: GM-55279
  • Agency: NHLBI NIH HHS, Id: HL-007824

Mesh Terms

  • Amino Acid Sequence
  • Animals
  • COS Cells
  • GTP-Binding Protein alpha Subunits, Gi-Go
  • GTPase-Activating Proteins
  • Humans
  • Molecular Sequence Data
  • Neurites
  • Proteasome Endopeptidase Complex
  • Receptor, Cannabinoid, CB1
  • rap1 GTP-Binding Proteins