Molecular mechanisms of dense-core vesicle release

致密核心囊泡释放的分子机制

基本信息

项目摘要

The secretion of growth factors, peptide hormones, neuropeptides and biogenic amines from dense-core vesicles (DCVs) in neurons and endocrine cells is a tightly-regulated event that drives physiological processes such as feeding, digestion, energy storage, lactation, emotion and analgesia. Compromised DCV release is implicated in metabolic and neurological disorders such as diabetes, eating disorders, depression, drug addiction, and Huntington’s disease. Yet the molecular pathways that govern the release of DCVs, particularly in electrically excitable cells of the nervous and endocrine systems, remain largely undefined. The objective of this proposal is to uncover molecular mechanisms that regulate DCV secretion. Our central hypothesis is that the signaling pathways that govern DCV release vary between different classes of cells, and between different populations of DCVs within the same cell, according to their selective expression and trafficking of key, as of yet unidentified regulatory molecules. We further posit that, similar to small synaptic vesicles, DCV release is tightly controlled by neuromodulatory signaling through G protein-coupled receptors (GPCRs). Our innovative hypothesis challenges the existing paradigm that focuses exclusively on intracellular calcium as the primary molecular determinant of DCV release. The discovery of diverse release mechanisms will provide a new understanding for long-standing questions surrounding the challenges associated with evoking neuropeptide secretion. We will test our hypothesis by addressing the following key knowledge gaps: 1) an understanding of the neural activity patterns and wide range of intracellular calcium concentrations that drive DCV release in different neuron classes, 2) and understanding of how neuromodulatory biochemical signaling can adjust the activity and/or calcium requirements for release, 3) elucidation of endogenous GPCRs that can carry out this novel form of neuromodulatory cross-talk, 4) elucidation of the diverse protein machineries associated with DCVs containing different cargoes in different cell classes. The proposed research builds on 1) our recent establishment of several assays for monitoring the actions of tachykinin and opioid neuropeptides in the striatum, 2) our recent discovery of diverse conditions for driving endogenous tachykinin and opioid neuropeptide release, 3) our successful development of photoactivatable peptides for mimicking, and thus calibrating, spatiotemporal aspects of endogenous release, and 4) the recent development of optical sensors that report peptide release in brain tissue. Uncovering the general principles that govern DCV release will establish new connections between intercellular and intracellular signaling pathways and reveal how they are integrated at the molecular level in numerous biological systems that transmit information via DCV secretion. In the long term, we anticipate that the unique signaling pathways uncovered can be exploited to treat metabolic diseases, psychological disorders and neurodegenerative disease, and for chronic pain, latter of which is urgently needed to address the Opioid Crisis. By uncovering new connections between signaling pathways that are fundamental to human physiology in both health and disease, the findings of this work will likely impact numerous scientific fields, including cancer, cardiology, development, gastroenterology, and neuroscience. 1
致密核心囊泡 (DCV) 分泌生长因子、肽激素、神经肽和生物胺 在神经元和内分泌细胞中,这是一个受到严格调控的事件,它驱动生理过程,例如进食、消化、 能量储存、哺乳、情绪和镇痛。 DCV 释放受损与代谢和神经系统相关 糖尿病、饮食失调、抑郁症、毒瘾和亨廷顿舞蹈症等疾病。然而分子 控制 DCV 释放的途径,特别是在神经和内分泌的电兴奋细胞中 系统,很大程度上仍未定义。该提案的目的是揭示调节 DCV 的分子机制 分泌。我们的中心假设是,控制 DCV 释放的信号通路在不同类别之间有所不同 细胞之间,以及同一细胞内不同 DCV 群体之间,根据它们的选择性表达和 迄今为止尚未确定的关键调节分子的贩运。我们进一步假设,与小突触小泡类似, DCV 的释放受到 G 蛋白偶联受体 (GPCR) 的神经调节信号的严格控制。我们的 创新假说挑战了现有的范式,该范式仅关注细胞内钙作为主要的 DCV 释放的分子决定因素。多样化释放机制的发现将提供新的认识 针对与诱发神经肽分泌相关的挑战的长期存在的问题。我们将测试我们的 通过解决以下关键知识差距来提出假设:1)了解神经活动模式和广泛的 不同神经元类别中驱动 DCV 释放的细胞内钙浓度范围,2) 以及对 神经调节生化信号如何调整释放的活性和/或钙需求,3) 阐明可以进行这种新型神经调节串扰的内源性 GPCR,4) 阐明 与包含不同细胞类别中不同货物的 DCV 相关的多种蛋白质机制。拟议的 研究建立在 1) 我们最近建立的几种监测速激肽和阿片类药物作用的测定方法的基础上 纹状体中的神经肽,2)我们最近发现驱动内源性速激肽的多种条件和 阿片类神经肽释放,3)我们成功开发了用于模仿的光激活肽,因此 校准、内源性释​​放的时空方面,以及 4) 报告光学传感器的最新发展 脑组织中肽的释放。揭示管理 DCV 发布的一般原则将建立新的联系 细胞间和细胞内信号通路之间的关系,并揭示它们如何在分子水平上整合 许多生物系统通过 DCV 分泌来传输信息。从长远来看,我们预计 发现的独特信号通路可用于治疗代谢疾病、心理障碍和 神经退行性疾病和慢性疼痛,后者是解决阿片类药物危机所迫切需要的。经过 揭示信号通路之间的新联系,这些信号通路对于人类健康和生理学至关重要 疾病,这项工作的发现可能会影响许多科学领域,包括癌症、心脏病学、发育、 胃肠病学和神经科学。 1

项目成果

期刊论文数量(0)
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Matthew R. Banghart其他文献

Switchable Proteins and Channels
可切换的蛋白质和通道
  • DOI:
    10.1002/9783527634408.ch15
  • 发表时间:
    2011
  • 期刊:
  • 影响因子:
    29
  • 作者:
    M. Volgraf;Matthew R. Banghart;D. Trauner
  • 通讯作者:
    D. Trauner
Photopharmacology: Controlling Native Voltage-Gated Ion Channels with Light
  • DOI:
    10.1016/j.bpj.2009.12.1143
  • 发表时间:
    2010-01-01
  • 期刊:
  • 影响因子:
  • 作者:
    Alexandre Mourot;Timm Fehrentz;Michael Kienzler;Ivan Tochitsky;Matthew R. Banghart;Dirk Trauner;Richard H. Kramer
  • 通讯作者:
    Richard H. Kramer
Light At The End Of The Channel: Photochromic Blockers For Optical Control Of Ion Channels In Individual Cells
  • DOI:
    10.1016/j.bpj.2008.12.836
  • 发表时间:
    2009-02-01
  • 期刊:
  • 影响因子:
  • 作者:
    Alexandre Mourot;Matthew R. Banghart;Doris L. Fortin;Dirk Trauner;Richard H. Kramer
  • 通讯作者:
    Richard H. Kramer
Nicotine is a Selective Pharmacological Chaperone of Acetylcholine Receptor Number and Stoichiometry. Implications for Drug Discovery
  • DOI:
    10.1208/s12248-009-9090-7
  • 发表时间:
    2009-03-12
  • 期刊:
  • 影响因子:
    3.700
  • 作者:
    Henry A. Lester;Cheng Xiao;Rahul Srinivasan;Cagdas D. Son;Julie Miwa;Rigo Pantoja;Matthew R. Banghart;Dennis A. Dougherty;Alison M. Goate;Jen C. Wang
  • 通讯作者:
    Jen C. Wang
Discovery Of Photochromic Ligands That Block Voltage-gated K+ Channels At The Internal TEA Binding Site
  • DOI:
    10.1016/j.bpj.2008.12.1022
  • 发表时间:
    2009-02-01
  • 期刊:
  • 影响因子:
  • 作者:
    Matthew R. Banghart;Alexandre Mourot;Doris L. Fortin;Richard H. Kramer;Dirk Trauner
  • 通讯作者:
    Dirk Trauner

Matthew R. Banghart的其他文献

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{{ truncateString('Matthew R. Banghart', 18)}}的其他基金

Development of opioid and ketamine probes for in vivo photopharmacology
用于体内光药理学的阿片类药物和氯胺酮探针的开发
  • 批准号:
    10401573
  • 财政年份:
    2022
  • 资助金额:
    $ 37.39万
  • 项目类别:
Next generation all-optical toolkits for functional analysis of neuropeptide dynamics in neural circuits
用于神经回路中神经肽动力学功能分析的下一代全光学工具包
  • 批准号:
    10394081
  • 财政年份:
    2021
  • 资助金额:
    $ 37.39万
  • 项目类别:
Next generation all-optical toolkits for functional analysis of neuropeptide dynamics in neural circuits
用于神经回路中神经肽动力学功能分析的下一代全光学工具包
  • 批准号:
    10201785
  • 财政年份:
    2019
  • 资助金额:
    $ 37.39万
  • 项目类别:
Next generation all-optical toolkits for functional analysis of neuropeptide dynamics in neural circuits
用于神经回路中神经肽动力学功能分析的下一代全光学工具包
  • 批准号:
    10426199
  • 财政年份:
    2019
  • 资助金额:
    $ 37.39万
  • 项目类别:
Next generation all-optical toolkits for functional analysis of neuropeptide dynamics in neural circuits
用于神经回路中神经肽动力学功能分析的下一代全光学工具包
  • 批准号:
    10093949
  • 财政年份:
    2019
  • 资助金额:
    $ 37.39万
  • 项目类别:
Molecular mechanisms of dense-core vesicle release
致密核心囊泡释放的分子机制
  • 批准号:
    10807380
  • 财政年份:
    2019
  • 资助金额:
    $ 37.39万
  • 项目类别:
Molecular mechanisms of dense-core vesicle release
致密核心囊泡释放的分子机制
  • 批准号:
    10189663
  • 财政年份:
    2019
  • 资助金额:
    $ 37.39万
  • 项目类别:
Molecular mechanisms of dense-core vesicle release
致密核心囊泡释放的分子机制
  • 批准号:
    10426137
  • 财政年份:
    2019
  • 资助金额:
    $ 37.39万
  • 项目类别:
Compartment-specific signaling of striatal opioid peptides in reward-guided behavior
奖励引导行为中纹状体阿片肽的区室特异性信号传导
  • 批准号:
    9378801
  • 财政年份:
    2017
  • 资助金额:
    $ 37.39万
  • 项目类别:
Compartment-Specific Signaling Of Striatal Opioid Peptides in Reward-Guided Behav
奖励引导行为中纹状体阿片肽的区室特异性信号传导
  • 批准号:
    8600669
  • 财政年份:
    2013
  • 资助金额:
    $ 37.39万
  • 项目类别:

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