Mechanism of cryptochrome-mediated photo transduction

隐花色素介导的光转导机制

基本信息

  • 批准号:
    8706189
  • 负责人:
  • 金额:
    $ 27.64万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2013
  • 资助国家:
    美国
  • 起止时间:
    2013-08-01 至 2017-05-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Our laboratory recently discovered that blue light photoactivation of insect Cryptochrome (Cry) cause rapid membrane depolarization and up to 300% increased action potential firing rate over baseline dark spontaneous firing in central brain neurons (Sheeba et al., 2007; Fogle et al., 2011). The electrophysiological light response is robust in the absence of all opsin-based classical photoreceptor inputs (Fogle et al., 2011). Genetically targeted expression of Cry in normally light-insensitive olfactory neurons confers electrophysiological light responsiveness, indicating that Cry expression may be used for optogenetic applications (Fogle et al., 2011). A combination of molecular-genetic and pharmacological experiments indicate that Cry's light sensitivity is mediated through light-activated changes in the redox state of the flavin adenine dinucleotide (FAD) chromophore bound to dCry which then couples to a redox sensor in cytoplasmic potassium channel subunits and modulate potassium channel activity. We propose to extend these findings by determining the precise molecular mechanism of how light activated Cry undergoes an intramolecular transfer of redox state from the flavin chromophore to the protein surface of Cry by testing mutants which lack a well conserved tri-tryptophan motif characterized in other Cry proteins as conducting redox signals. We will then test the hypothesis that redox transfer takes place to target proteins in the membrane. Based on strong preliminary data that membrane coupling of Cry's light activated redox state occurs through voltage gated potassium channels, we will test the hypothesis that dCry then interacts with membrane redox-sensitive effector Hyperkinetic beta subunit (Hk) of voltage-gated potassium (Kv) channels. Our preliminary data indicates that light activation of Cry rapidly modulates cellular potassium currents and depolarizes the membrane potential. We have begun testing this hypothesis and find that the lLNv electrophysiological light response in almost completely abolished in Hk null mutant flies, suggesting that Hk is the primary membrane target for the novel dCry-based phototransduction mechanism. We will determine whether rapid translocation of dCry to the neuronal membrane increases the speed and the amplitude of the electrophysiological light response, as tested using a chemical biology-based inducible strategy. These experiments provide a unique opportunity to unravel a novel non-opsin phototransduction mechanism based on redox sensing. We have also the first opportunity to examine real-time actions of Cry in vivo and the possibility of determining a biological function for the highly conserved redox sensor in KvBeta subunits. As Cry's chromophore, FAD, is the ubiquitously expressed, our work may provide the basis of a new "Vitamin B-based" optogenetic technology applicable to cells that do not synthesize adequate levels of retinal.
描述(由申请人提供):我们的实验室最近发现,昆虫隐花色素(Cry)的蓝光光激活会导致膜快速去极化,并且与中枢神经元的基线暗自发放电相比,动作电位放电率增加高达 300%(Sheeba 等人,2007 年;Fogle 等人,2011 年)。在没有所有基于视蛋白的经典光感受器输入的情况下,电生理光响应是稳健的(Fogle 等人,2011)。通常对光不敏感的嗅觉神经元中 Cry 的基因靶向表达赋予电生理光响应性,表明 Cry 表达可用于光遗传学应用(Fogle 等,2011)。分子遗传学和药理学实验相结合表明,Cry 的光敏感性是通过与 dCry 结合的黄素腺嘌呤二核苷酸 (FAD) 生色团的氧化还原状态的光激活变化来介导的,然后与细胞质钾通道亚基中的氧化还原传感器偶联并调节钾通道活性。我们建议通过测试缺乏在其他 Cry 蛋白中传导氧化还原信号的良好保守三色氨酸基序的突变体,确定光激活的 Cry 如何经历从黄素发色团到 Cry 蛋白表面的氧化还原态分子内转移的精确分子机制,从而扩展这些发现。然后我们将测试氧化还原转移发生到膜中的目标蛋白质的假设。基于 Cry 光激活氧化还原态的膜耦合通过电压门控钾通道发生的强有力的初步数据,我们将测试 dCry 随后与电压门控钾 (Kv) 通道的膜氧化还原敏感效应器 Hyperkinetic beta 亚基 (Hk) 相互作用的假设。我们的初步数据表明,Cry 的光激活可快速调节细胞钾电流并使膜电位去极化。我们已经开始测试这一假设,发现 Hk 无效突变果蝇中的 lLNv 电生理光反应几乎完全消失,这表明 Hk 是基于 dCry 的新型光转导机制的主要膜靶点。我们将确定 dCry 快速易位到神经元膜是否会增加电生理光反应的速度和幅度,正如使用基于化学生物学的诱导策略所测试的那样。这些实验为揭示基于氧化还原传感的新型非视蛋白光转导机制提供了独特的机会。我们还首次有机会检查 Cry 在体内的实时作用,以及确定 KvBeta 亚基中高度保守的氧化还原传感器的生物功能的可能性。由于 Cry 的发色团 FAD 是普遍表达的,我们的工作可能为一种新的“基于维生素 B”的光遗传学技术提供基础,该技术适用于不能合成足够水平视网膜的细胞。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Todd C Holmes其他文献

Todd C Holmes的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Todd C Holmes', 18)}}的其他基金

UV to blue neuronal phototransduction mechanisms
紫外到蓝色神经元光转导机制
  • 批准号:
    10621560
  • 财政年份:
    2018
  • 资助金额:
    $ 27.64万
  • 项目类别:
UV to blue neuronal phototransduction mechanisms
紫外到蓝色神经元光转导机制
  • 批准号:
    10374057
  • 财政年份:
    2018
  • 资助金额:
    $ 27.64万
  • 项目类别:
UV to blue neuronal phototransduction mechanisms
紫外到蓝色神经元光转导机制
  • 批准号:
    10388927
  • 财政年份:
    2018
  • 资助金额:
    $ 27.64万
  • 项目类别:
UV to blue neuronal phototransduction mechanisms
紫外到蓝色神经元光转导机制
  • 批准号:
    9900018
  • 财政年份:
    2018
  • 资助金额:
    $ 27.64万
  • 项目类别:
Mechanism of cryptochrome-mediated photo transduction
隐花色素介导的光转导机制
  • 批准号:
    8502106
  • 财政年份:
    2013
  • 资助金额:
    $ 27.64万
  • 项目类别:
Ultraviolet light sensing by cryptochrome
隐花色素紫外光传感
  • 批准号:
    8852650
  • 财政年份:
    2013
  • 资助金额:
    $ 27.64万
  • 项目类别:
Ultraviolet light sensing by cryptochrome
隐花色素紫外光传感
  • 批准号:
    8705550
  • 财政年份:
    2013
  • 资助金额:
    $ 27.64万
  • 项目类别:
Ultraviolet light sensing by cryptochrome
隐花色素紫外光传感
  • 批准号:
    8560888
  • 财政年份:
    2013
  • 资助金额:
    $ 27.64万
  • 项目类别:
Mechanism of cryptochrome-mediated photo transduction
隐花色素介导的光转导机制
  • 批准号:
    9090139
  • 财政年份:
    2013
  • 资助金额:
    $ 27.64万
  • 项目类别:
Ultraviolet light sensing by cryptochrome
隐花色素紫外光传感
  • 批准号:
    9066498
  • 财政年份:
    2013
  • 资助金额:
    $ 27.64万
  • 项目类别:

相似海外基金

Acute senescence: a novel host defence counteracting typhoidal Salmonella
急性衰老:对抗伤寒沙门氏菌的新型宿主防御
  • 批准号:
    MR/X02329X/1
  • 财政年份:
    2024
  • 资助金额:
    $ 27.64万
  • 项目类别:
    Fellowship
Transcriptional assessment of haematopoietic differentiation to risk-stratify acute lymphoblastic leukaemia
造血分化的转录评估对急性淋巴细胞白血病的风险分层
  • 批准号:
    MR/Y009568/1
  • 财政年份:
    2024
  • 资助金额:
    $ 27.64万
  • 项目类别:
    Fellowship
Combining two unique AI platforms for the discovery of novel genetic therapeutic targets & preclinical validation of synthetic biomolecules to treat Acute myeloid leukaemia (AML).
结合两个独特的人工智能平台来发现新的基因治疗靶点
  • 批准号:
    10090332
  • 财政年份:
    2024
  • 资助金额:
    $ 27.64万
  • 项目类别:
    Collaborative R&D
Cellular Neuroinflammation in Acute Brain Injury
急性脑损伤中的细胞神经炎症
  • 批准号:
    MR/X021882/1
  • 财政年份:
    2024
  • 资助金额:
    $ 27.64万
  • 项目类别:
    Research Grant
KAT2A PROTACs targetting the differentiation of blasts and leukemic stem cells for the treatment of Acute Myeloid Leukaemia
KAT2A PROTAC 靶向原始细胞和白血病干细胞的分化,用于治疗急性髓系白血病
  • 批准号:
    MR/X029557/1
  • 财政年份:
    2024
  • 资助金额:
    $ 27.64万
  • 项目类别:
    Research Grant
Combining Mechanistic Modelling with Machine Learning for Diagnosis of Acute Respiratory Distress Syndrome
机械建模与机器学习相结合诊断急性呼吸窘迫综合征
  • 批准号:
    EP/Y003527/1
  • 财政年份:
    2024
  • 资助金额:
    $ 27.64万
  • 项目类别:
    Research Grant
FITEAML: Functional Interrogation of Transposable Elements in Acute Myeloid Leukaemia
FITEAML:急性髓系白血病转座元件的功能研究
  • 批准号:
    EP/Y030338/1
  • 财政年份:
    2024
  • 资助金额:
    $ 27.64万
  • 项目类别:
    Research Grant
STTR Phase I: Non-invasive focused ultrasound treatment to modulate the immune system for acute and chronic kidney rejection
STTR 第一期:非侵入性聚焦超声治疗调节免疫系统以治疗急性和慢性肾排斥
  • 批准号:
    2312694
  • 财政年份:
    2024
  • 资助金额:
    $ 27.64万
  • 项目类别:
    Standard Grant
ロボット支援肝切除術は真に低侵襲なのか?acute phaseに着目して
机器人辅助肝切除术真的是微创吗?
  • 批准号:
    24K19395
  • 财政年份:
    2024
  • 资助金额:
    $ 27.64万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Collaborative Research: Changes and Impact of Right Ventricle Viscoelasticity Under Acute Stress and Chronic Pulmonary Hypertension
合作研究:急性应激和慢性肺动脉高压下右心室粘弹性的变化和影响
  • 批准号:
    2244994
  • 财政年份:
    2023
  • 资助金额:
    $ 27.64万
  • 项目类别:
    Standard Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了