TY - JOUR
T1 - Cannabinoid receptor-induced neurite outgrowth is mediated by Rap1 activation through Gαo/i-triggered proteasomal degradation of Rap1GAPII
AU - Jordan, J. Dedrick
AU - He, John Cijiang
AU - Eungdamrong, Narat J.
AU - Gomes, Ivone
AU - Ali, Wasif
AU - Nguyen, Tracy
AU - Bivona, Trever G.
AU - Philips, Mark R.
AU - Devi, Lakshmi A.
AU - Iyengar, Ravi
PY - 2005/3/25
Y1 - 2005/3/25
N2 - The Gαo/i-coupled CB1 cannabionoid receptor induces neurite outgrowth in Neuro-2A cells. The mechanisms of signaling through Gαo/i to induce neurite outgrowth were studied. The expression of Gαo/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. Gαo/i- induced activation of endogenous Rap1 in Neuro-2A cells is blocked by the proteasomal inhibitor lactacystin. Gαo/i stimulates neurite outgrowth that is blocked by the expression of dominant negative Rap1. Expression of Hap1GAPII also blocks the Gαo/i-induced neurite outgrowth and treatment with proteasomal inhibitors potentiates this inhibition. The endogenous Gαo/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 Gαo/i-coupled cannabinoid receptor, by regulating the proteasomal degradation of Rap1GAPII, activates Rap1 to induce neurite outgrowth.
AB - The Gαo/i-coupled CB1 cannabionoid receptor induces neurite outgrowth in Neuro-2A cells. The mechanisms of signaling through Gαo/i to induce neurite outgrowth were studied. The expression of Gαo/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. Gαo/i- induced activation of endogenous Rap1 in Neuro-2A cells is blocked by the proteasomal inhibitor lactacystin. Gαo/i stimulates neurite outgrowth that is blocked by the expression of dominant negative Rap1. Expression of Hap1GAPII also blocks the Gαo/i-induced neurite outgrowth and treatment with proteasomal inhibitors potentiates this inhibition. The endogenous Gαo/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 Gαo/i-coupled cannabinoid receptor, by regulating the proteasomal degradation of Rap1GAPII, activates Rap1 to induce neurite outgrowth.
UR - http://www.scopus.com/inward/record.url?scp=20144381647&partnerID=8YFLogxK
U2 - 10.1074/jbc.M411521200
DO - 10.1074/jbc.M411521200
M3 - Article
C2 - 15657046
AN - SCOPUS:20144381647
SN - 0021-9258
VL - 280
SP - 11413
EP - 11421
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 12
ER -