Hahm Jeong-Hoon, Kim Sunhee, Paik Young-Ki
Department of Biochemistry, Yonsei Proteome Research Center, Yonsei University, Seoul, Korea.
Aging Cell. 2009 Aug;8(4):473-83. doi: 10.1111/j.1474-9726.2009.00495.x. Epub 2009 May 31.
G-proteins, including GPA-3, play an important role in regulating physiological responses in Caenorhabditis elegans. When confronted with an environmental stimulus such as dauer pheromone, or poor nutrients, C. elegans receives and integrates external signals through its nervous system (i.e. amphid neurons), which interprets and translates them into biological action. Here it is shown that a suppressed neuronal cGMP level caused by GPA-3 activation leads to a significant increase (47.3%) in the mean lifespan of adult C. elegans through forkhead transcription factor family O (FOXO)-mediated signal. A reduced neuronal cGMP level was found to be caused by an increased cGMP-specific phosphodiesterase activity at the transcriptional level. Our results using C. elegans mutants with specific deficits in TGF-beta and FOXO RNAi system suggest a mechanism in that cGMP, TGF-beta, and FOXO signaling interact to differentially produce the insulin-like molecules, ins-7 and daf-28, causing suppression of the insulin/IGF-1 pathway and promoting lifespan extension. Our findings provide not only a new mechanism of cGMP-mediated induction of longevity in adult C. elegans but also a possible therapeutic strategy for neuronal disease, which has been likened to brain diabetes.
包括GPA-3在内的G蛋白在调节秀丽隐杆线虫的生理反应中发挥着重要作用。当遇到诸如 dauer 信息素或营养匮乏等环境刺激时，秀丽隐杆线虫通过其神经系统（即嗅觉神经元）接收并整合外部信号，该神经系统对这些信号进行解释并将其转化为生物学行动。本文表明，由GPA-3激活导致的神经元cGMP水平抑制通过叉头转录因子O家族（FOXO）介导的信号，使成年秀丽隐杆线虫的平均寿命显著增加（47.3%）。发现神经元cGMP水平降低是由转录水平上cGMP特异性磷酸二酯酶活性增加所致。我们使用在TGF-β和FOXO RNAi系统中具有特定缺陷的秀丽隐杆线虫突变体的研究结果表明，cGMP、TGF-β和FOXO信号相互作用，以不同方式产生胰岛素样分子ins-7和daf-28，从而抑制胰岛素/IGF-1途径并促进寿命延长。我们的研究结果不仅揭示了成年秀丽隐杆线虫中cGMP介导的长寿诱导新机制, 还为神经元疾病提供了一种可能的治疗策略，神经元疾病已被比作脑糖尿病。
