Pre- and postsynaptic pathways underlying the stress response in the adrenal medulla
肾上腺髓质应激反应的突触前和突触后通路
基本信息
- 批准号:10207848
- 负责人:
- 金额:$ 35.94万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-09-01 至 2021-12-31
- 项目状态:已结题
- 来源:
- 关键词:AcetylcholineAdrenal MedullaAffinityArousalBiogenic AminesBlood CirculationCardiacCardiovascular systemCatecholaminesCell secretionCellsCharacteristicsChargeChromaffin CellsChromaffin granuleCoupledCyclic AMPCytoplasmic GranulesDataDynaminElectrophysiology (science)EmotionalEventExocytosisFiberFrequenciesG-Protein-Coupled ReceptorsGTP-Binding Protein alpha Subunits, GsGuanosine Triphosphate PhosphohydrolasesHormone secretionHormonesHumanHypoglycemiaImageIn SituIn VitroInjuryLaboratoriesLeadLinkLungMeasuresMental HealthMetabolicModalityMolecularNeuronsNeurotransmittersOutputPathway interactionsPeptidesPharmacologyPhysiologicalPropertyProteinsPsyche structurePublic HealthReactionReceptor ActivationRegulationResearchRoleSignal PathwaySignal TransductionSliceSplanchnic NervesStimulusStressSympathetic Nervous SystemSynapsesSynaptic plasticityTestingTimeTotal Internal Reflection FluorescentTrainingTranslatingVariantVeinsbiological adaptation to stresscholinergicdesensitizationfightinginsightnatural hypothermianovel therapeuticspeptide hormonephospholipase C epsilonpituitary adenylate cyclase activating polypeptidepituitary adenylate cyclase-activating peptide receptorpostsynapticpresynapticreceptorrespiratoryresponsesensorstressorsynaptotagminsynaptotagmin VIItool
项目摘要
ABSTRACT
The “fight-or-flight” response refers to the state of heightened physiological and mental arousal triggered by a
physical threat, emotionally charged event, or metabolic disturbance. Although the precise reaction to each
stressor may vary, all share some basic characteristics of sympathetic nervous system activation.
Adrenomedullary chromaffin cells are core effectors of the sympathetic response in the periphery. When
activated during stress, they discharge a cocktail of hormones into the suprarenal vein for circulation
throughout the body. These hormones modulate cardiac, pulmonary, and metabolic functions in ways that
favor survival or maintain internal conditions when they are threatened. Secretion from the adrenal medulla is
dependent on input from preganglionic splanchnic fibers, which release acetylcholine (ACh) and pituitary
adenylate cyclase-activating polypeptide (PACAP) onto chromaffin cells. What remains poorly understood is
how ACh and PACAP tune hormone release to accommodate the range of splanchnic firing frequencies
associated with variations in sympathetic tone. Three Specific Aims are proposed to fill this gap in our
understanding of the stress response pathway. The Aims will test the overall hypothesis that variations in
presynaptic splanchnic input are translated by different receptor-coupled pathways in chromaffin cells to
dynamically regulate the amount of hormone output. Aim 1 builds on recent preliminary data that shows, for
the first time, a role for any synaptotagmin (Syt) at the splanchnic-chromaffin cell synapse. Planned studies,
using in situ slice electrophysiology, will define the role of Ca2+ sensing at this synapse, and evaluate the idea
that synaptic facilitation, regulated by Syt7, amplifies hormone discharge from chromaffin cells when
splanchnic fibers discharge at high frequencies. Aim 2 is motivated by preliminary data that shows
Phospholipase C-epsilon (PLC) is required for transducing PACAP stimulation into Ca2+ signals in chromaffin
cells that cause exocytosis. PACAP is thought to underlie chromaffin cell secretion during stress. This has
prompted us to posit that with increased splanchnic firing frequencies that produce facilitation, PLC activity in
chromaffin cells must be “turned on” to sustain increases in hormone output. Aim 3 builds on data which shows
that PACAP stimulates exocytosis in chromaffin cells, but does so while paradoxically restricting the release of
peptide hormones packaged within a chromaffin granule. Relevant for the differential release of biogenic
amines and hormone peptides, we will characterize the properties of PACAP-stimulated fusion pores and
investigate mechanisms by which they are constrained. We expect these studies will provide a coherent
molecular and physiological framework for understanding how presynaptic activity, postsynaptic receptor-
coupled signaling pathways, and exocytosis are mechanistically linked to regulate the stress response.
摘要
“战或逃”反应指的是由一种刺激所引发的增强的生理和精神唤醒状态。
身体威胁、情绪化事件或代谢紊乱。虽然对每一个人的确切反应
应激源可能不同,但都具有交感神经系统激活一些基本特征。
肾上腺髓质嗜铬细胞是外周交感神经反应的核心效应细胞。当
它们在压力下被激活,向肾上腺静脉释放激素混合物,促进血液循环
在整个身体。这些激素调节心脏、肺和代谢功能,
有利于生存或维持内部条件时,他们受到威胁。肾上腺髓质的分泌物
依赖于来自节前内脏神经纤维的输入,其释放乙酰胆碱(ACh)和垂体
腺苷酸环化酶激活多肽(PACAP)的作用。人们仍然不太了解的是,
乙酰胆碱和PACAP如何调节激素释放以适应内脏放电频率的范围
与交感神经张力的变化有关。我们提出了三个具体目标,以填补这一空白,
了解压力反应途径。目标将检验总体假设,
突触前内脏输入由嗜铬细胞中不同的受体偶联途径翻译,
动态调节激素的分泌量。目标1建立在最近的初步数据基础上,这些数据显示,
第一次,任何突触结合蛋白(Syt)在内脏嗜铬细胞突触的作用。计划的研究,
使用原位切片电生理学,将定义在该突触处的Ca 2+感知的作用,并评估该想法
突触易化,由Syt 7调节,放大了嗜铬细胞的激素分泌,
内脏纤维以高频率放电。目标2的动机是初步数据显示,
磷脂酶C-β(PLC β)是将PACAP刺激信号转化为嗜铬细胞内Ca ~(2+)信号所必需的
引起胞吐作用的细胞。PACAP被认为是压力下嗜铬细胞分泌的基础。这
提示我们,随着内脏放电频率的增加,产生促进作用,PLC抑制了活动,
嗜铬细胞必须被“打开”以维持激素输出的增加。目标3建立在数据基础上,
PACAP刺激嗜铬细胞的胞吐作用,但同时矛盾地限制了
嗜铬颗粒内包裹的肽激素。与生物源的差异释放有关
胺和激素肽,我们将表征PACAP刺激的融合孔的性质,
研究它们被限制的机制。我们希望这些研究将提供一个连贯的
分子和生理学的框架来理解突触前活动,突触后受体,
偶联的信号传导途径和胞吐作用在机制上与调节应激反应相关。
项目成果
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Food deprivation induces presynaptic plasticity in the autonomic nervous system.
食物匮乏会引起自主神经系统的突触前可塑性。
- DOI:10.1073/pnas.1605618113
- 发表时间:2016
- 期刊:
- 影响因子:11.1
- 作者:Holz,RonaldW;Anantharam,Arun
- 通讯作者:Anantharam,Arun
Integrating Optical and Electrochemical Approaches to Assess the Actions of Dynamin at the Fusion Pore.
综合光学和电化学方法来评估 Dynamin 在融合孔中的作用。
- DOI:10.1007/978-1-0716-0676-6_12
- 发表时间:2020
- 期刊:
- 影响因子:0
- 作者:Smith,KatherineA;Prantzalos,EmilyR;Anantharam,Arun
- 通讯作者:Anantharam,Arun
The high-affinity calcium sensor synaptotagmin-7 serves multiple roles in regulated exocytosis.
- DOI:10.1085/jgp.201711944
- 发表时间:2018-06-04
- 期刊:
- 影响因子:0
- 作者:MacDougall DD;Lin Z;Chon NL;Jackman SL;Lin H;Knight JD;Anantharam A
- 通讯作者:Anantharam A
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Arun Anantharam其他文献
Arun Anantharam的其他文献
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{{ truncateString('Arun Anantharam', 18)}}的其他基金
Pre and post-synaptic pathways underlying the stress response in the adrenal medulla
肾上腺髓质应激反应的突触前和突触后通路
- 批准号:
10609941 - 财政年份:2022
- 资助金额:
$ 35.94万 - 项目类别:
Pre and post-synaptic pathways underlying the stress response in the adrenal medulla
肾上腺髓质应激反应的突触前和突触后通路
- 批准号:
10576623 - 财政年份:2022
- 资助金额:
$ 35.94万 - 项目类别:
The Impact of Synaptotagmin Isoform Structure and Diversity on Dense Core Granule Exocytosis
突触结合蛋白亚型结构和多样性对致密核心颗粒胞吐作用的影响
- 批准号:
9330872 - 财政年份:2015
- 资助金额:
$ 35.94万 - 项目类别:
The Impact of Synaptotagmin Isoform Structure and Diversity on Dense Core Granule Exocytosis
突触结合蛋白亚型结构和多样性对致密核心颗粒胞吐作用的影响
- 批准号:
9132314 - 财政年份:2015
- 资助金额:
$ 35.94万 - 项目类别:
Secretion-associated dynamic of the plasma membrane
质膜的分泌相关动态
- 批准号:
7949977 - 财政年份:2009
- 资助金额:
$ 35.94万 - 项目类别:
Secretion-associated dynamic of the plasma membrane
质膜的分泌相关动态
- 批准号:
7674348 - 财政年份:2009
- 资助金额:
$ 35.94万 - 项目类别:
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