期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 280, 期 12, 页码 11413-11421出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M411521200
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资金
- NHLBI NIH HHS [HL-007824] Funding Source: Medline
- NIDA NIH HHS [DA-08863, DA-05798, DA-00458] Funding Source: Medline
- NIGMS NIH HHS [GM-55279, GM-54508] Funding Source: Medline
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.
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