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.
Jordan
J Dedrick
JD
Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, New York, New York 10029, USA.
He
John Cijiang
JC
Eungdamrong
Narat J
NJ
Gomes
Ivone
I
Ali
Wasif
W
Nguyen
Tracy
T
Bivona
Trever G
TG
Philips
Mark R
MR
Devi
Lakshmi A
LA
Iyengar
Ravi
R
D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000502:physiology*; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D016501:Neurites / Q000502:physiology*; D046988:Proteasome Endopeptidase Complex / Q000502:physiology*; D043884:Receptor, Cannabinoid, CB1 / Q000502:physiology*; D020827:rap1 GTP-Binding Proteins / Q000502:physiology*
D020690:GTPase-Activating Proteins; C484658:RAP1GAP protein, human; D043884:Receptor, Cannabinoid, CB1; D046988:Proteasome Endopeptidase Complex; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D020827:rap1 GTP-Binding Proteins