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PTK2 regulates tau-induced neurotoxicity via phosphorylation of p62 at Ser403. PTK2通过p62 Ser403位点的磷酸化调节tau诱导的神经毒性。
IF 1.9 4区 医学 Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-03-01 DOI: 10.1080/01677063.2022.2114471
Shinrye Lee, Myungjin Jo, Younghwi Kwon, Yu-Mi Jeon, Seyeon Kim, Kea Joo Lee, Hyung-Jun Kim

Tau is a microtubule-associated protein that forms insoluble filaments that accumulate as neurofibrillary tangles in neurodegenerative diseases such as Alzheimer's disease and other related tauopathies. A relationship between abnormal Tau accumulation and ubiquitin-proteasome system impairment has been reported. However, the molecular mechanism linking Tau accumulation and ubiquitin proteasome system (UPS) dysfunction remains unclear. Here, we show that overexpression of wild-type or mutant (P301L) Tau increases the abundance of polyubiquitinated proteins and activates the autophagy-lysosome pathway in mammalian neuronal cells. Previous studies found that PTK2 inhibition mitigates toxicity induced by UPS impairment. Thus, we investigated whether PTK2 inhibition can attenuate Tau-induced UPS impairment and cell toxicity. We found that PTK2 inhibition significantly reduces Tau-induced death in mammalian neuronal cells. Moreover, overexpression of WT or mutant Tau increased the phosphorylation levels of PTK2 and p62. We also confirmed that PTK2 inhibition suppresses Tau-induced phosphorylation of PTK2 and p62. Furthermore, PTK2 inhibition significantly attenuated the climbing defect and shortened the lifespan in the Drosophila model of tauopathy. In addition, we observed that phosphorylation of p62 is markedly increased in Alzheimer's disease patients with tauopathies. Taken together, our results indicate that the UPS dysfunction induced by Tau accumulation might contribute directly to neurodegeneration in tauopathies and that PTK2 could be a promising therapeutic target for tauopathies.

Tau是一种微管相关蛋白,在神经退行性疾病(如阿尔茨海默病和其他相关的Tau病)中形成不溶性细丝,以神经原纤维缠结的形式积累。异常Tau积累与泛素-蛋白酶体系统损伤之间的关系已被报道。然而,连接Tau积累和泛素蛋白酶体系统(UPS)功能障碍的分子机制尚不清楚。在这里,我们发现野生型或突变型(P301L) Tau的过表达增加了哺乳动物神经元细胞中多泛素化蛋白的丰度,并激活了自噬-溶酶体途径。先前的研究发现,抑制PTK2可减轻UPS损伤引起的毒性。因此,我们研究了PTK2抑制是否可以减轻tau诱导的UPS损伤和细胞毒性。我们发现,PTK2抑制显著降低tau诱导的哺乳动物神经元细胞死亡。此外,过表达WT或突变型Tau增加了PTK2和p62的磷酸化水平。我们还证实,PTK2抑制抑制tau诱导的PTK2和p62磷酸化。此外,PTK2抑制显著减轻了果蝇的攀爬缺陷,缩短了果蝇的寿命。此外,我们观察到p62的磷酸化在伴有牛头病变的阿尔茨海默病患者中显着增加。综上所述,我们的研究结果表明,Tau积累诱导的UPS功能障碍可能直接导致牛头病的神经退行性变,而PTK2可能是牛头病的一个有希望的治疗靶点。
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引用次数: 2
Evaluation of mouse behavioral responses to nutritive versus nonnutritive sugar using a deep learning-based 3D real-time pose estimation system. 使用基于深度学习的三维实时姿态估计系统评估小鼠对营养糖和非营养糖的行为反应。
IF 1.9 4区 医学 Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-03-01 DOI: 10.1080/01677063.2023.2174982
Jineun Kim, Dae-Gun Kim, Wongyo Jung, Greg S B Suh

Animals are able to detect the nutritional content of sugar independently of taste. When given a choice between nutritive sugar and nonnutritive sugar, animals develop a preference for nutritive sugar over nonnutritive sugar during a period of food deprivation (Buchanan et al., 2022; Dus et al., 2011; 2015; Tan et al., 2020; Tellez et al., 2016). To quantify behavioral features during an episode of licking nutritive versus nonnutritive sugar, we implemented a multi-vision, deep learning-based 3D pose estimation system, termed the AI Vision Analysis for Three-dimensional Action in Real-Time (AVATAR)(Kim et al., 2022). Using this method, we found that mice exhibit significantly different approach behavioral responses toward nutritive sugar versus nonnutritive sugar even before licking a sugar solution. Notably, the behavioral sequences during the approach toward nutritive versus nonnutritive sugar became significantly different over time. These results suggest that the nutritional value of sugar not only promotes its consumption but also elicits distinct repertoires of feeding behavior in deprived mice.

动物能够独立于味道检测出糖的营养成分。当在营养糖和非营养糖之间做出选择时,动物在食物剥夺期间会对营养糖而不是非营养糖产生偏好(Buchanan et al., 2022;Dus等,2011;2015;Tan et al., 2020;Tellez等人,2016)。为了量化舔营养糖和非营养糖时的行为特征,我们实施了一个多视觉、基于深度学习的3D姿势估计系统,称为实时三维动作人工智能视觉分析(AVATAR)(Kim等人,2022)。使用这种方法,我们发现即使在舔糖溶液之前,小鼠对营养糖和非营养糖的接近行为反应也有显著差异。值得注意的是,在摄入营养糖和非营养糖的过程中,行为序列随着时间的推移变得明显不同。这些结果表明,糖的营养价值不仅促进了糖的消耗,而且在被剥夺的小鼠中引起了不同的摄食行为。
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引用次数: 1
Inter-organ regulation by the brain in Drosophila development and physiology. 果蝇发育和生理中大脑的器官间调节。
IF 1.9 4区 医学 Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-03-01 DOI: 10.1080/01677063.2022.2137162
Sunggyu Yoon, Mingyu Shin, Jiwon Shim

The brain plays an essential role in regulating physiological homeostasis by communicating with other organs. Neuronal cells either directly innervate target tissues and transmit signals or secrete systemic factors into the hemolymph to regulate bodily functions, including physiology, development, metabolism, and immunity. In this review, we discuss the systemic functions of inter-organ communication mediated by the brain in four distinct categories: (1) nutrient sensing and feeding, (2) gastrointestinal activity and metabolism, (3) development and metamorphosis, and (4) immunity and hematopoiesis. First, we describe how chemosensory signals are sensed and transmitted to the brain in Drosophila and how the brain stimulates or modifies feeding behavior. Second, we summarize the brain-organ axis that regulates appetite activities and neuroendocrine pathways that maintain metabolic homeostasis. Third, we discuss how overall development in Drosophila is achieved by insulin and how it affects ecdysone signaling to initiate pupariation. Finally, we discuss how the central or peripheral nervous system controls hematopoiesis and innate immunity in Drosophila larvae. Given the functional parallels between Drosophila and humans, homologous pathways are likely to be conserved in human development and disease models, and the fly model system will continue to provide mechanistic insights into understanding complex interactions.

大脑通过与其他器官的交流在调节生理稳态中起着至关重要的作用。神经细胞可以直接支配目标组织并传递信号,也可以向血淋巴分泌系统因子来调节身体机能,包括生理、发育、代谢和免疫。在这篇综述中,我们从四个不同的方面讨论了由大脑介导的器官间通讯的系统功能:(1)营养感知和摄食,(2)胃肠活动和代谢,(3)发育和变态,(4)免疫和造血。首先,我们描述了化学感觉信号在果蝇中是如何被感知并传递到大脑的,以及大脑是如何刺激或改变摄食行为的。其次,我们总结了调节食欲活动的脑器官轴和维持代谢稳态的神经内分泌途径。第三,我们讨论了果蝇的整体发育是如何通过胰岛素实现的,以及胰岛素如何影响蜕皮激素信号来启动蛹期。最后,我们讨论了中枢或周围神经系统如何控制果蝇幼虫的造血和先天免疫。鉴于果蝇和人类在功能上的相似之处,同源通路可能在人类发育和疾病模型中是保守的,而果蝇模型系统将继续为理解复杂的相互作用提供机制上的见解。
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引用次数: 1
Circadian gating of light-induced arousal in Drosophila sleep. 果蝇睡眠中光诱导觉醒的昼夜节律门控。
IF 1.9 4区 医学 Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-03-01 DOI: 10.1080/01677063.2022.2151596
Hoyeon Lee, Chunghun Lim

Circadian rhythms and sleep homeostasis constitute the two-process model for daily sleep regulation. However, evidence for circadian control of sleep-wake cycles has been relatively short since clock-less animals often show sleep behaviors quantitatively comparable to wild-type. Here we examine Drosophila sleep behaviors under different light-dark regimes and demonstrate that circadian clocks gate light-induced arousal. Genetic excitation of tyrosine decarboxylase 2 (TDC2)-expressing neurons suppressed sleep more evidently at night, causing nocturnal activity. The arousal effects were likely mediated in part by glutamate transmission from the octopaminergic neurons and substantially masked by light. Application of T12 cycles (6-h light: 6-h dark) further showed that the light-sensitive effects of TDC2 neurons depended on the time of the day. In particular, light-sensing via visual input pathway led to strong sleep suppression at subjective night, and such an effect disappeared in clock-less mutants. Transgenic mapping revealed that light-induced arousal and free-running behavioral rhythms require distinct groups of circadian pacemaker neurons. These results provide convincing evidence that circadian control of sleep is mediated by the dedicated clock neurons for light-induced arousal.

昼夜节律和睡眠稳态构成了日常睡眠调节的双过程模型。然而,昼夜节律控制睡眠-觉醒周期的证据相对较短,因为无生物钟动物通常表现出与野生型动物相当的睡眠行为。在这里,我们研究了果蝇在不同的光-暗制度下的睡眠行为,并证明昼夜节律钟控制了光诱导的觉醒。表达酪氨酸脱羧酶2 (TDC2)的神经元的基因兴奋在夜间更明显地抑制睡眠,引起夜间活动。唤醒效应可能部分是由来自章鱼胺能神经元的谷氨酸传递介导的,并且基本上被光线掩盖。T12周期(6小时光照:6小时黑暗)的应用进一步表明,TDC2神经元的光敏效应依赖于一天中的时间。特别是,通过视觉输入通路的光感导致主观夜晚强烈的睡眠抑制,而这种效应在无时钟突变体中消失。转基因图谱显示,光诱导的觉醒和自由运行的行为节律需要不同的昼夜节律起搏器神经元群。这些结果提供了令人信服的证据,表明睡眠的昼夜节律控制是由专门用于光诱导唤醒的时钟神经元介导的。
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引用次数: 1
TERT distal promoter GC islands are critical for telomerase and together with DNMT3B silencing may serve as a senescence-inducing agent in gliomas. TERT远端启动子GC岛对端粒酶至关重要,与DNMT3B沉默一起可能作为胶质瘤的衰老诱导剂。
IF 1.9 4区 医学 Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2022-09-01 DOI: 10.1080/01677063.2022.2106371
Naz Şerifoğlu, Begün Erbaba, Michelle M Adams, Ayça Arslan-Ergül

Telomerase is reactivated in the majority of cancers. For instance, in gliomas, it is common that the TERT promoter is mutated. Research on telomere promoter GC islands have been focused primarily on proximal TERT promoter but little is known about the distal promoter. Therefore, in this study, we investigated the proximal and distal TERT promoter, in terms of DNA methylation. We did bisulfite sequencing in zebrafish tissue samples for the distal tert promoter. In the zebrafish brain tissues, we identified a hypomethylation site in the tert promoter, and found that this hypomethylation was associated with aging and shortened telomeres. Through site directed mutagenesis in glioma cell lines, we changed 10 GC spots individually, cloned into a reporter vector, and measured promoter activity. Finally, we silenced DNMT3B and measured telomerase activity along with vidaza and adriamycin treatments. Site directed mutagenesis of glioma cell lines revealed that each of the 10 GC spots are critical for telomerase activity. Changing GC to AT abolished promoter activity in all spots when transfected into glioma cell lines. Then, through silencing of DNMT3B, we observed a reduction in hTERT expression levels, while hTR remained the same, and a major increase in senescence-associated beta-galactosidase activity. Finally, we propose a model regarding the efficacy of two chemotherapeutic drugs, adriamycin and azacytidine, on gliomas. Here, we show that distal TERT promoter is critical; changing even one GC to AT abolishes TERT promoter activity. DNMT3B, a de novo methyltransferase, together with GC islands in distal TERT promoter plays an important role in regulation of telomerase expression and senescence.

端粒酶在大多数癌症中被重新激活。例如,在神经胶质瘤中,TERT启动子发生突变是很常见的。对端粒启动子GC岛的研究主要集中在TERT近端启动子上,而对远端启动子知之甚少。因此,在本研究中,我们从DNA甲基化的角度研究了TERT近端启动子和远端启动子。我们在斑马鱼组织样本中对远端启动子进行亚硫酸盐测序。在斑马鱼脑组织中,我们在tert启动子中发现了一个低甲基化位点,并发现这种低甲基化与衰老和端粒缩短有关。通过对胶质瘤细胞系的定点诱变,我们分别改变了10个GC点,克隆成报告载体,并测量了启动子活性。最后,我们沉默DNMT3B并测量端粒酶活性以及维达扎和阿霉素治疗。神经胶质瘤细胞系的定点突变表明,10个GC点中的每一个都对端粒酶活性至关重要。将GC改为AT,转染到胶质瘤细胞系后,所有点的启动子活性都被破坏。然后,通过沉默DNMT3B,我们观察到hTERT表达水平降低,而hTR保持不变,衰老相关的β -半乳糖苷酶活性显著增加。最后,我们提出了一个关于两种化疗药物阿霉素和阿扎胞苷对胶质瘤疗效的模型。在这里,我们表明远端TERT启动子是关键的;即使将一个GC更改为AT也会消除TERT启动子活性。DNMT3B是一种新的甲基转移酶,与TERT远端启动子中的GC岛一起在端粒酶表达和衰老的调控中起重要作用。
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引用次数: 0
An expansion of phenotype: novel homozygous variant in the MED17 identified in patients with progressive microcephaly and global developmental delay. 表型扩展:在进行性小头畸形和整体发育迟缓患者中发现的MED17新纯合变异
IF 1.9 4区 医学 Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2022-09-01 DOI: 10.1080/01677063.2022.2149748
Rafiullah Rafiullah, Alia M Albalawi, Sultan R Alaradi, Majed Alluqmani, Muhammad Mushtaq, Abdul Wali, Sulman Basit

Global developmental delay (GDD) is a lifelong disability that affects 1-3% of the population around the globe. It is phenotypically variable and highly heterogeneous in terms of the underlying genetics. Patients with GDD are intellectually disabled (ID) manifesting cognitive impairment and deficient adaptive behavior. Here, we investigated a two-looped consanguineous family segregating severe ID, seizure, and progressive microcephaly. Magnetic resonance imaging (MRI) of the brain showed mild brain atrophy and myelination defect. Whole exome sequencing (WES) was performed on the DNA samples of two patients and a novel homozygous missense variant (Chr11:g0.93528085; NM_004268.5_c.871T > C; p. Trp291Gly) was identified in the MED17 gene. Sanger sequencing revealed that the identified variant is heterozygous in both parents and healthy siblings. This variant is conserved among different species, causes a non-conserved amino acid change, and is predicted deleterious by various in silico tools. The variant is not reported in population variant databases. MED17 (OMIM: 613668) encodes for the mediator of RNA polymerase II transcription complex subunit 17. Structure modeling of MED17 protein revealed that Trp291 is involved in different inter-helical interactions, providing structural stability. Replacement of Trp291Gly, a less hydrophobic amino acid loses the inter-helical interaction leading to a perturb variant of MED17 protein.

全球发育迟缓(GDD)是一种影响全球1-3%人口的终身残疾。它在表型上是可变的,在潜在的遗传学方面是高度异质的。GDD患者是智力残疾(ID),表现为认知障碍和适应行为缺陷。在这里,我们调查了一个分离严重ID,癫痫发作和进行性小头畸形的双环近亲家庭。脑核磁共振显示轻度脑萎缩及髓鞘缺损。对2例患者的DNA样本进行全外显子组测序(WES),发现一种新的纯合错义变异(Chr11:g0.93528085;NM_004268.5_c.871T > C;p. Trp291Gly)在MED17基因中被鉴定。Sanger测序显示,鉴定的变异在父母和健康的兄弟姐妹中都是杂合的。这种变异在不同的物种中是保守的,引起非保守的氨基酸变化,并且通过各种硅工具预测是有害的。该变异未在种群变异数据库中报告。MED17 (OMIM: 613668)编码RNA聚合酶II转录复合物亚基17的中介。MED17蛋白的结构建模显示,Trp291参与了不同的螺旋间相互作用,提供了结构稳定性。替代Trp291Gly,疏水性较低的氨基酸失去螺旋间相互作用,导致MED17蛋白的扰动变体。
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引用次数: 0
Possible association between the lrrk2 gene and anxiety behavior: a systematic literature review. lrrk2基因与焦虑行为之间可能存在的关联:一项系统的文献综述。
IF 1.9 4区 医学 Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2022-09-01 DOI: 10.1080/01677063.2022.2144293
R E Moreira-Júnior, R M Souza, J G de Carvalho, J P Bergamini, A L Brunialti-Godard

Alterations to the LRRK2 gene have been associated with Parkinson's disease and alcohol consumption in animals and humans. Furthermore, these disorders are strongly related to anxiety disorders (ADs). Thus, we investigated how the LRRK2 gene might influence anxiety in humans and mice. We elaborated a systematic review based on the PRISMA Statement of studies that investigated levels of anxiety in animal or human models with alterations in the LRRK2 gene. The search was conducted in the PubMed, Scopus, and Web of Science databases, and in reference lists with descriptors related to ADs and the LRRK2. From the 62 articles assessed for eligibility, 16 were included: 11 conducted in humans and seven, in mice. Lrrk2 KO mice and the LRRK2 G2019S, LRRK2 R1441G, and LRRK2 R1441C variants were addressed. Five articles reported an increase in anxiety levels concerning the LRRK2 variants. Decreased anxiety levels were observed in two articles, one focusing on the LRRK2 G2019S and the other, on the Lrrk2 KO mice. Eight other articles reported no differences in anxiety levels in individuals with Lrrk2 alterations compared to their healthy controls. This study discusses a possible influence between the LRRK2 gene and anxiety, adding information to the existing knowledge respecting the influence of genetics on anxiety.

在动物和人类中,LRRK2基因的改变与帕金森病和饮酒有关。此外,这些障碍与焦虑症(ADs)密切相关。因此,我们研究了LRRK2基因如何影响人类和小鼠的焦虑。我们根据PRISMA声明对LRRK2基因改变的动物或人类模型的焦虑水平进行了系统回顾。在PubMed、Scopus和Web of Science数据库中进行搜索,并在带有与ad和LRRK2相关描述符的参考文献列表中进行搜索。在62篇合格评估的文章中,包括16篇:11篇在人类身上进行,7篇在小鼠身上进行。Lrrk2 KO小鼠以及Lrrk2 G2019S、Lrrk2 R1441G和Lrrk2 R1441C变体进行了研究。五篇文章报道了与LRRK2变异相关的焦虑水平增加。两篇文章观察到焦虑水平下降,一篇关注LRRK2 G2019S,另一篇关注LRRK2 KO小鼠。其他八篇文章报道,与健康对照组相比,Lrrk2变异个体的焦虑水平没有差异。本研究探讨了LRRK2基因与焦虑之间可能存在的影响,为现有关于遗传对焦虑影响的知识增加了信息。
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引用次数: 2
Knockdown of PHLDA2 promotes apoptosis and autophagy of glioma cells through the AKT/mTOR pathway. PHLDA2的下调通过AKT/mTOR通路促进胶质瘤细胞凋亡和自噬。
IF 1.9 4区 医学 Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2022-03-01 DOI: 10.1080/01677063.2022.2096023
Chengyong Guo, Shuo Liu, Tao Zhang, Jipeng Yang, Zhaohui Liang, Shengkui Lu

Pleckstrin homology like domain family A member 2 (PHLDA2) is an imprinted gene expressed in placenta and has been shown to be associated with tumor progression. However, the effect of PHLDA2 on glioma cell growth has not been reported yet. Data based on TCGA database showed that PHLDA2 was up-regulated in glioma tissues. Moreover, PHLDA2 was also elevated in glioma cells. Functional assays showed that siRNA-mediated knockdown of PHLDA2 reduced cell viability of glioma cells and suppressed the cell proliferation. Cell apoptosis of glioma cells was promoted by silencing of PHLDA2 with increased Bax and decreased Bcl-2. Silencing of PHLDA2 reduced protein expression of p62, enhanced LC3 and Beclin1 to promote autophagy. Phosphorylated AKT and mTOR were down-regulated in glioma cells by interference of PHLDA2. In conclusion, downregulation of PHLDA2 inhibited glioma cell proliferation, and promoted cell apoptosis and autophagy through inactivation of AKT/mTOR signaling.

Pleckstrin homology like domain family A member 2 (PHLDA2)是一种在胎盘中表达的印迹基因,已被证明与肿瘤进展有关。然而,PHLDA2对胶质瘤细胞生长的影响尚未见报道。基于TCGA数据库的数据显示,PHLDA2在胶质瘤组织中表达上调。此外,PHLDA2在胶质瘤细胞中也升高。功能分析显示,sirna介导的PHLDA2敲低可降低胶质瘤细胞的活力,抑制细胞增殖。沉默PHLDA2可促进胶质瘤细胞凋亡,Bax升高,Bcl-2降低。PHLDA2的沉默降低了p62蛋白的表达,增强了LC3和Beclin1的表达,促进了自噬。磷酸化AKT和mTOR在胶质瘤细胞中通过PHLDA2的干扰下调。综上所述,下调PHLDA2可抑制胶质瘤细胞增殖,并通过抑制AKT/mTOR信号通路促进细胞凋亡和自噬。
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引用次数: 0
The light-activated TRP channel: the founding member of the TRP channel superfamily. 光激活TRP通道:TRP通道超家族的创始成员。
IF 1.9 4区 医学 Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2022-03-01 DOI: 10.1080/01677063.2022.2121824
Baruch Minke, William L Pak

The Drosophila light-activated Transient Receptor Potential (TRP) channel is the founding member of a large and diverse family of channel proteins. The Drosophila TRP (dTRP) channel, which generates the electrical response to light has been investigated in a great detail two decades before the first mammalian TRP channel was discovered. Thus, dTRP is unique among members of the TRP channel superfamily because its physiological role and the enzymatic cascade underlying its activation are established. In this article we outline the research leading to elucidation of dTRP as the light activated channel and focus on a major physiological property of the dTRP channel, which is indirect activation via a cascade of enzymatic reactions. These detailed pioneering studies, based on the genetic dissection approach, revealed that light activation of the Drosophila TRP channel is mediated by G-Protein-Coupled Receptor (GPCR)-dependent enzymatic cascade, in which phospholipase C β (PLC) is a crucial component. This physiological mechanism of Drosophila TRP channel activation was later found in mammalian TRPC channels. However, the initial studies on the mammalian TRPV1 channel indicated that it is activated directly by capsaicin, low pH and hot temperature (>42 °C). This mechanism of activation was apparently at odds with the activation mechanism of the TRPC channels in general and the Drosophila light activated TRP/TRPL channels in particular, which are target of a GPCR-activated PLC cascade. Subsequent studies have indicated that under physiological conditions TRPV1 is also target of a GPCR-activated PLC cascade in the generation of inflammatory pain. The Drosophila light-activated TRP channel is still a useful experimental paradigm because its physiological function as the light-activated channel is known, powerful genetic techniques can be applied to its further analysis, and signaling molecules involved in the activation of these channels are available.

果蝇光激活瞬时受体电位(TRP)通道是一个庞大而多样的通道蛋白家族的创始成员。果蝇TRP (dTRP)通道产生对光的电反应,早在第一个哺乳动物TRP通道被发现的20年前,人们就对其进行了详细的研究。因此,在TRP通道超家族的成员中,dTRP是独一无二的,因为它的生理作用和激活它的酶级联是确定的。在本文中,我们概述了导致阐明dTRP作为光激活通道的研究,并重点介绍了dTRP通道的一个主要生理特性,即通过一系列酶促反应间接激活。这些详细的开创性研究,基于遗传解剖方法,揭示了果蝇TRP通道的光激活是由g蛋白偶联受体(GPCR)依赖性酶级联介导的,其中磷脂酶C β (PLC)是一个关键组成部分。果蝇TRP通道激活的这种生理机制后来在哺乳动物TRPC通道中被发现。然而,对哺乳动物TRPV1通道的初步研究表明,它直接被辣椒素、低pH和高温(>42°C)激活。这种激活机制显然与一般的TRPC通道的激活机制不一致,特别是果蝇光激活的TRP/TRPL通道,它们是gpcr激活的PLC级联的目标。随后的研究表明,在生理条件下,TRPV1也是gpcr激活的PLC级联反应产生炎性疼痛的靶标。果蝇光激活TRP通道仍然是一个有用的实验范例,因为它作为光激活通道的生理功能是已知的,强大的遗传技术可以应用于其进一步分析,并且参与这些通道激活的信号分子是可用的。
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引用次数: 3
The force-from-lipid principle and its origin, a 'what is true for E. coli is true for the elephant' refrain. 脂质作用原理及其起源,“对大肠杆菌适用的道理对大象也适用”。
IF 1.9 4区 医学 Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2022-03-01 DOI: 10.1080/01677063.2022.2097674
Boris Martinac, Ching Kung

The force-from-lipid (FFL) principle states that it is the lateral stretch force from the lipid membrane that ultimately opens mechanosensitive (MS) channels, not the external tether nor the internal cytoskeleton. Piezo channels for certain touch or proprioception and the hair-cell channels for hearing or balance apparently obey this principle, which is based on the idea that the lipid bilayer is an amphipathic compartment with a distinct internal force-distribution profile. Physical stretch or insertion of chemical impurities alters this profile, driving channel shape change to conform to the new environment. Thus, FFL governs all dynamic proteins embedded in membrane, including Kv's and TRPs. This article retraces the humble origin of the FFL concept. Paramecium research first created the mind set and the resources to electrically explore other microbial membranes. Patch clamp revealed MS-channel activities from yeast and E. coli spheroplasts. Despite formidable obstacles against interdisciplinary research, the E. coli MS-channel protein, MscL, was purified through fractionation by following its activity, much like enzyme purification. Reconstituted into a simple lipid bilayer, pure MscL retains mechanosensitivity, thus firmly establishing the FFL principle in 1994. The relatively simple MscL and its functional cousin MscS soon became ideal models for detailed analyses. Like the DNA-RNA-protein 'central dogma' or ATP synthesis, FFL is a fundamental principle, which appeared early in evolution, retained in all cellular life forms, and is expected to contribute to future molecular research on sensations, homeostasis, and embryonic development.

脂质力(FFL)原理指出,最终打开机械敏感(MS)通道的是来自脂质膜的侧向拉伸力,而不是外部系索或内部细胞骨架。用于某些触觉或本体感觉的压电通道和用于听力或平衡的毛细胞通道显然遵循这一原则,这一原则是基于脂质双分子层是具有独特内力分布特征的两亲性隔室的观点。物理拉伸或化学杂质的插入改变了这种轮廓,驱动通道形状改变以适应新的环境。因此,FFL控制着嵌入膜中的所有动态蛋白,包括Kv和TRPs。本文回顾了FFL概念的卑微起源。草履虫的研究首先创造了用电探索其他微生物膜的思维模式和资源。膜片钳显示酵母和大肠杆菌球质体的ms通道活性。尽管跨学科研究存在巨大障碍,但大肠杆菌ms通道蛋白(MscL)通过跟踪其活性的分离纯化,就像酶纯化一样。纯MscL重组为简单的脂质双分子层,保留了机械敏感性,从而在1994年确立了FFL原理。相对简单的间充质干细胞及其功能性的同类间充质干细胞很快成为详细分析的理想模型。就像dna - rna -蛋白质的“中心法则”或ATP合成一样,FFL是一个基本原理,出现在进化的早期,保留在所有细胞生命形式中,并有望为未来的感觉、体内平衡和胚胎发育的分子研究做出贡献。
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引用次数: 8
期刊
Journal of neurogenetics
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