Cell-Autonomous Gβ Signaling Defines Neuron-Specific Steady State Serotonin Synthesis in Caenorhabditis elegans.
Cell-Autonomous Gβ Signaling Defines Neuron-Specific Steady State Serotonin Synthesis in Caenorhabditis elegans.
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DOI：
10.1371/journal.pgen.1005540
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发表时间：
2015-09
期刊：
影响因子：
4.5
通讯作者：
Sze JY
中科院分区：
文献类型：
--
作者：
Xu L;Choi S;Xie Y;Sze JY
异三聚体G蛋白通过特定的细胞内效应器调节大量细胞功能。越来越多的药理学和生物化学研究表明，Gβ亚基除了在调节Gα亚基活性中发挥作用外，还作为信号分子与广泛的效应物直接相互作用以调节下游细胞反应。然而，Gβ介导的信号通路在体内的天然生物学作用仅在少数情况下被表征。在此，我们通过对秀丽隐杆线虫5-HT合成突变体的遗传筛选，确定了一条在特定的多巴胺能神经元中起作用的Gβ GPB-1信号通路，以定义稳态5-HT合成。我们发现，通过细胞自主GPB-1的OCR-2 TRPV通道的信号定义的5-HT合成酶色氨酸羟化酶tph-1在ADF化学感觉神经元的基线表达。该Gβ信号通路对于确定肾上腺素能细胞命运不是必需的，并且在机制上与应激诱导的tph-1上调分离。我们发现，ADF产生的5-HT控制特定的先天节律行为。这些结果揭示了Gβ介导的信号传导在分化细胞中起作用以指定内在功能特性，并表明基线TPH表达不是默认的一般性多巴胺能命运，而是在成熟神经系统中以细胞特异性方式编程。TPH表达的细胞特异性调节可能是功能不同的神经元中定制的稳态5-HT合成及其先天行为调节的一般原则。神经递质5-羟色胺的合成水平在进化的不同生物体中形成不同的行为，但在功能不同的神经元类型中定义稳态5-羟色胺合成的机制仍然未知。对秀丽隐杆线虫中神经元特异性5-羟色胺合成突变体的遗传筛选揭示了在特定的多巴胺能神经元中起作用的独特的Gβ GPB-1信号通路，以确定5-羟色胺合成限速酶色氨酸羟化酶tph-1的基线表达。与Gα亚基驱动下游效应物的典型异源三聚体G蛋白信号传导途径不同，我们发现通过Gβ GPB-1到OCR-2 TRPV通道的信号传导定义了基线tph-1表达。这种Gβ信号传导不是建立或维持多巴胺能细胞命运所必需的，而是致力于在成熟神经元中设定稳态5-HT合成。行为分析表明，5-HT在不同的神经元合成调节不同的先天节律行为。我们的工作确定了一个Gβ介导的信号通路在分化的神经元细胞中运作，以指定内在的功能性功能障碍，并阐明了在专用行为回路中神经元特异性稳态5-HT合成的遗传编程的机制原理。
Heterotrimeric G proteins regulate a vast array of cellular functions via specific intracellular effectors. Accumulating pharmacological and biochemical studies implicate Gβ subunits as signaling molecules interacting directly with a wide range of effectors to modulate downstream cellular responses, in addition to their role in regulating Gα subunit activities. However, the native biological roles of Gβ-mediated signaling pathways in vivo have been characterized only in a few cases. Here, we identified a Gβ GPB-1 signaling pathway operating in specific serotonergic neurons to the define steady state serotonin (5-HT) synthesis, through a genetic screen for 5-HT synthesis mutants in Caenorhabditis elegans. We found that signaling through cell autonomous GPB-1 to the OCR-2 TRPV channel defines the baseline expression of 5-HT synthesis enzyme tryptophan hydroxylase tph-1 in ADF chemosensory neurons. This Gβ signaling pathway is not essential for establishing the serotonergic cell fates and is mechanistically separated from stress-induced tph-1 upregulation. We identified that ADF-produced 5-HT controls specific innate rhythmic behaviors. These results revealed a Gβ-mediated signaling operating in differentiated cells to specify intrinsic functional properties, and indicate that baseline TPH expression is not a default generic serotonergic fate, but is programmed in a cell-specific manner in the mature nervous system. Cell-specific regulation of TPH expression could be a general principle for tailored steady state 5-HT synthesis in functionally distinct neurons and their regulation of innate behavior. Levels of neurotransmitter serotonin synthesis shape disparate behaviors in evolutionary diverse organisms, but the mechanisms defining steady state serotonin synthesis in functionally distinct neuronal types remain unknown. A genetic screen for neuron-specific serotonin synthesis mutants in Caenorhabditis elegans revealed a unique Gβ GPB-1 signaling pathway operating in specific serotonergic neurons to define the baseline expression of serotonin synthesis rate-limiting enzyme tryptophan hydroxylase tph-1. Unlike in canonical heterotrimeric G protein signaling pathways where Gα subunits drive downstream effectors, we found that signaling through Gβ GPB-1 to the OCR-2 TRPV channel defines the baseline tph-1 expression. This Gβ signaling is not required for the establishment or maintenance of the serotonergic cell fates, but dedicated to set steady state 5-HT synthesis in mature neurons. Behavioral analyses showed that 5-HT synthesized in different neurons modulates distinct innate rhythmic behaviors. Our work identified a Gβ-mediated signaling pathway operating in differentiated neuronal cells to specify intrinsic functional diversities, and illuminate a mechanistic principle for genetic programming of neuron-specific steady state 5-HT synthesis in dedicated behavioral circuits.