title: Gamma-aminobutyric acid induces tumor cells apoptosis via GABABR1·β-arrestins·JNKs signaling module.
abstract: Gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter in central nervous system, has yet been found to widely exist in tumor tissues to regulate tumor cells growth. However, the function of GABA on inducing tumor cells apoptosis and the potential mechanism are still unclear. In order to detect whether GABA via GABAB receptor GABABR1 would activate c-Jun N-terminal kinases (JNKs) to promote tumor cells apoptosis, co-immunoprecipitation assay was used to investigate the association of β-arrestins with GABABR1 and JNKs in the different four cancer cell lines. Our observation demonstrated that β-arrestins, in addition to their role in G protein-coupled receptors desensitization, had an additional function as adapter proteins to recruit JNKs to GABABR1, thereby conferring distinct enzymatic activities upon the receptor, which may trigger JNKs signal pathway involved in the regulation of cellular growth. Activated JNKs subsequently phosphorylated downstream c-Jun to transcribe a wide variety of pro-apoptotic genes. Additionally, GABA up-regulated the ratio of pro-apoptotic protein Bax to anti-apoptotic protein Bcl-2, and thus facilitated caspase-3 cleavage, leading to tumor cells apoptosis in a mitochondrial-dependent pathway. In contrast, GABABR antagonist CGP35348 reversed GABA-induced JNKs phosphorylation and its downstream proteins activation, which consequently restrained tumor cells apoptosis. Taken together, our study suggested that GABA via its receptor GABABR1 recruited β-arrestins to facilitate the activation of JNKs cascade, resulting in tumor cells growth inhibition.
authors.affiliation: Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical College, 84 West Huai-hai Road, Xuzhou, 221002, Jiangsu, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Tian
authors.forename: Jin-Xia
authors.initials: JX
authors.lastname: Wu
authors.forename: Feng-Xiao
authors.initials: FX
authors.lastname: Shan
authors.forename: Shang-Nuan
authors.initials: SN
authors.lastname: Zhang
authors.forename: Qian
authors.initials: Q
authors.lastname: Cheng
authors.forename: Jun-Nian
authors.initials: JN
authors.lastname: Zheng
authors.forename: Dong-Sheng
authors.initials: DS
authors.lastname: Pei
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D019390:Arrestins / Q000378:metabolism*; D018682:GABA Agents / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D018080:Receptors, GABA-B / Q000378:metabolism*; D015290:Second Messenger Systems; D000071557:beta-Arrestins; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
chemical_list: D019390:Arrestins; D018682:GABA Agents; D018080:Receptors, GABA-B; D000071557:beta-Arrestins; D005680:gamma-Aminobutyric Acid; D048670:MAP Kinase Kinase 4