title: Cannabinoid receptor-induced neurite outgrowth is mediated by Rap1 activation through G(alpha)o/i-triggered proteasomal degradation of Rap1GAPII.
abstract: 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.
authors.affiliation: Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, New York, New York 10029, USA.
authors.forename: J Dedrick
authors.initials: JD
authors.lastname: Jordan
authors.forename: John Cijiang
authors.initials: JC
authors.lastname: He
authors.forename: Narat J
authors.initials: NJ
authors.lastname: Eungdamrong
authors.forename: Ivone
authors.initials: I
authors.lastname: Gomes
authors.forename: Wasif
authors.initials: W
authors.lastname: Ali
authors.forename: Tracy
authors.initials: T
authors.lastname: Nguyen
authors.forename: Trever G
authors.initials: TG
authors.lastname: Bivona
authors.forename: Mark R
authors.initials: MR
authors.lastname: Philips
authors.forename: Lakshmi A
authors.initials: LA
authors.lastname: Devi
authors.forename: Ravi
authors.initials: R
authors.lastname: Iyengar
mesh_terms: 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*
chemical_list: 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