A TRPV channel modulates C. elegans neurosecretion, larval starvation survival, and adult lifespan.
A TRPV channel modulates C. elegans neurosecretion, larval starvation survival, and adult lifespan.
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DOI：
10.1371/journal.pgen.1000213
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发表时间：
2008-10
期刊：
影响因子：
4.5
通讯作者：
Ashrafi, Kaveh
中科院分区：
文献类型：
--
作者：
Lee, Brian H.;Ashrafi, Kaveh
对于大多数生物来说，食物只能断断续续地获得；因此，将营养可获得性的感觉与生长和发育结合起来的分子机制对生存至关重要。然而，这些机制仍然没有得到很好的界定。在缺乏营养的情况下，新孵化的第一幼虫(L1)阶段秀丽线虫停止发育，并在这种状态下存活数周。我们分离了UNC-31的突变，它编码了一种钙激活的神经致密核心囊泡释放调节因子，这有助于提高饥饿存活率。这种延长的存活期与daf-2胰岛素信号缺陷突变体中的情况类似，并最终依赖于daf-16，它编码一种FOXO转录因子，其活性受到胰岛素信号的抑制。虽然胰岛素信号调节新陈代谢、成年寿命和Dauer的形成，但也调节这些过程的胰岛素非依赖性机制并不促进饥饿生存，这表明调节饥饿生存是一个独特的程序。细胞特异性救援实验发现了一小部分初级感觉神经元，其中UNC-31重建调节了饥饿存活，表明这些神经元介导了对食物可获得性的感知。我们发现，OCR-2，一种定位于这一亚群神经元纤毛的瞬时受体潜在香草素(TRPV)通道，调节多肽激素的分泌和L1饥饿的存活。此外，OCR-2的失活会显著延长成年人的寿命。这些发现表明，TRPV通道通过调节神经致密核心囊泡的分泌，调节对各种有害的、热的、渗透的和机械刺激的感觉，将营养的有效性与幼虫的饥饿存活率和成虫的寿命联系在一起。饥饿是大多数生物体在其自然环境中遇到的一种常见的生理状态。然而，使生物体能够准确感知营养供应并相应地匹配其能量需求的分子机制还没有被很好地理解。为了阐明这些机制，我们在线虫中分离出突变体，这些突变体在饥饿时比野生型动物存活时间长约50%。对于一个这样的突变体，我们发现延长存活率是由于UNC-31基因的突变，该基因在神经系统中发挥作用，介导包括胰岛素在内的神经内分泌信号分子的释放。虽然这个基因在神经系统中广泛表达，但我们发现它的活性在一小部分感觉神经元中是必需的，以调节饥饿的生存。这些神经元具有纤毛末梢，在检测环境线索方面发挥作用。这些纤毛的破坏，或定位于这些纤毛的TRPV通道的失活，模拟了营养剥夺导致延长饥饿生存的感觉，这依赖于胰岛素调节的转录因子。这一通道的中断也延长了成年人的寿命。综上所述，我们的发现揭示了TRPV通道将营养信号与神经内分泌相结合，神经内分泌反过来决定了成虫的寿命和幼虫的饥饿存活。
For most organisms, food is only intermittently available; therefore, molecular mechanisms that couple sensation of nutrient availability to growth and development are critical for survival. These mechanisms, however, remain poorly defined. In the absence of nutrients, newly hatched first larval (L1) stage Caenorhabditis elegans halt development and survive in this state for several weeks. We isolated mutations in unc-31, encoding a calcium-activated regulator of neural dense-core vesicle release, which conferred enhanced starvation survival. This extended survival was reminiscent of that seen in daf-2 insulin-signaling deficient mutants and was ultimately dependent on daf-16, which encodes a FOXO transcription factor whose activity is inhibited by insulin signaling. While insulin signaling modulates metabolism, adult lifespan, and dauer formation, insulin-independent mechanisms that also regulate these processes did not promote starvation survival, indicating that regulation of starvation survival is a distinct program. Cell-specific rescue experiments identified a small subset of primary sensory neurons where unc-31 reconstitution modulated starvation survival, suggesting that these neurons mediate perception of food availability. We found that OCR-2, a transient receptor potential vanilloid (TRPV) channel that localizes to the cilia of this subset of neurons, regulates peptide-hormone secretion and L1 starvation survival. Moreover, inactivation of ocr-2 caused a significant extension in adult lifespan. These findings indicate that TRPV channels, which mediate sensation of diverse noxious, thermal, osmotic, and mechanical stimuli, couple nutrient availability to larval starvation survival and adult lifespan through modulation of neural dense-core vesicle secretion. Starvation is a common physiological condition encountered by most organisms in their natural environments. However, the molecular mechanisms that allow organisms to accurately sense nutrient availability and match their energetic demands accordingly are not well understood. To elucidate these mechanisms, we isolated mutants in C. elegans that survive about 50% longer than wild-type animals when starved. For one such mutant, we found that the extended survival was due to mutation in the unc-31 gene, which functions in the nervous system to mediate release of neuroendocrine signaling molecules including insulin. Although this gene is broadly expressed in the nervous system, we found that its activity is required in a small subset of sensory neurons to regulate starvation survival. These neurons have ciliated endings that function in detection of environmental cues. Disruption of these cilia, or inactivation of a TRPV channel localized to these cilia, mimicked the perception of nutrient deprivation leading to extended starvation survival, which is dependent on an insulin-regulated transcription factor. Disruption of this channel also extended adult lifespan. Taken together, our findings reveal that TRPV channels couple nutritional cues to neuroendocrine secretion, which in turn determines adult lifespan and larval starvation survival.
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DOI：
10.1016/j.bbrc.2004.06.149
发表时间：
2004-08-11
影响因子：
3.1
作者：
Akiba, Y;Kato, S;Hibi, T
通讯作者：
Hibi, T
影响因子：
7.8
作者：
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影响因子：
16.2
作者：
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通讯作者：
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影响因子：
9.2
作者：
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通讯作者：
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影响因子：
3.4
作者：
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通讯作者：
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