Istituto di Genetica e Biofisica A, IGB, CNR, Consiglio Nazionale delle Ricerche, Napoli, Italy.
BMC Biol. 2010 Nov 11;8:138. doi: 10.1186/1741-7007-8-138.
Polymodal, nociceptive sensory neurons are key cellular elements of the way animals sense aversive and painful stimuli. In Caenorhabditis elegans, the polymodal nociceptive ASH sensory neurons detect aversive stimuli and release glutamate to generate avoidance responses. They are thus useful models for the nociceptive neurons of mammals. While several molecules affecting signal generation and transduction in ASH have been identified, less is known about transmission of the signal from ASH to downstream neurons and about the molecules involved in its modulation.
We discovered that the regulator of G protein signalling (RGS) protein, EGL-10, is required for appropriate avoidance responses to noxious stimuli sensed by ASH. As it does for other behaviours in which it is also involved, egl-10 interacts genetically with the G(o)/(i)α protein GOA-1, the G(q)α protein EGL-30 and the RGS EAT-16. Genetic, behavioural and Ca²(+) imaging analyses of ASH neurons in live animals demonstrate that, within ASH, EGL-10 and GOA-1 act downstream of stimulus-evoked signal transduction and of the main transduction channel OSM-9. EGL-30 instead appears to act upstream by regulating Ca²(+) transients in response to aversive stimuli. Analysis of the delay in the avoidance response, of the frequency of spontaneous inversions and of the genetic interaction with the diacylglycerol kinase gene, dgk-1, indicate that EGL-10 and GOA-1 do not affect signal transduction and neuronal depolarization in response to aversive stimuli but act in ASH to modulate downstream transmission of the signal.
The ASH polymodal nociceptive sensory neurons can be modulated not only in their capacity to detect stimuli but also in the efficiency with which they respond to them. The Gα and RGS molecules studied in this work are conserved in evolution and, for each of them, mammalian orthologs can be identified. The discovery of their role in the modulation of signal transduction and signal transmission of nociceptors may help us to understand how pain is generated and how its control can go astray (such as chronic pain) and may suggest new pain control therapies.
多模式伤害感受神经元是动物感知厌恶和疼痛刺激的关键细胞元件。在秀丽隐杆线虫中，多模式伤害感受 ASH 感觉神经元检测到厌恶刺激，并释放谷氨酸以产生回避反应。因此，它们是哺乳动物伤害感受神经元的有用模型。虽然已经确定了几种影响 ASH 中信号产生和转导的分子，但对于信号从 ASH 传递到下游神经元以及参与其调节的分子知之甚少。
我们发现，G 蛋白信号调节因子（RGS）蛋白 EGL-10 对于 ASH 感知到的有害刺激的适当回避反应是必需的。与它参与的其他行为一样，egl-10 在遗传上与 G(o)/(i)α 蛋白 GOA-1、G(q)α 蛋白 EGL-30 和 RGS EAT-16 相互作用。对活体动物中 ASH 神经元的遗传、行为和 Ca²(+)成像分析表明，在 ASH 中，EGL-10 和 GOA-1 作用于刺激引发的信号转导下游和主要转导通道 OSM-9 之后。相反，EGL-30 似乎通过调节对厌恶刺激的 Ca²(+)瞬变来发挥上游作用。对回避反应的延迟、自发反转的频率以及与二酰基甘油激酶基因 dgk-1 的遗传相互作用的分析表明，EGL-10 和 GOA-1 不影响对厌恶刺激的信号转导和神经元去极化，但在 ASH 中作用于信号的下游传递。
多模式伤害感受 ASH 感觉神经元不仅可以调节其检测刺激的能力，还可以调节其对刺激的反应效率。在这项工作中研究的 Gα 和 RGS 分子在进化中是保守的，并且可以鉴定出它们各自的哺乳动物同源物。发现它们在伤害感受器信号转导和信号传递的调节中的作用可能有助于我们了解疼痛是如何产生的，以及其控制如何出错（如慢性疼痛），并可能为新的疼痛控制疗法提供启示。
