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：
Arun Anantharam
金额：
$ 35.94万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
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：
https://reporter.nih.gov/project-details/10207848
关键词：
Acetylcholine Adrenal Medulla Affinity Arousal Biogenic Amines Blood Circulation Cardiac Cardiovascular system Catecholamines Cell secretion Cells Characteristics Charge Chromaffin Cells Chromaffin granule Coupled Cyclic AMP Cytoplasmic Granules Data Dynamin Electrophysiology (science)Emotional Event Exocytosis Fiber Frequencies G-Protein-Coupled Receptors GTP-Binding Protein alpha Subunits, Gs Guanosine Triphosphate Phosphohydrolases Hormone secretion Hormones Human Hypoglycemia Image In Situ In Vitro Injury Laboratories Lead Link Lung Measures Mental Health Metabolic Modality Molecular Neurons Neurotransmitters Output Pathway interactions Peptides Pharmacology Physiological Property Proteins Psyche structure Public Health Reaction Receptor Activation Regulation Research Role Signal Pathway Signal Transduction Slice Splanchnic Nerves Stimulus Stress Sympathetic Nervous System Synapses Synaptic plasticity Testing Time Total Internal Reflection Fluorescent Training Translating Variant Veins biological adaptation to stress cholinergic desensitization fighting insight natural hypothermia novel therapeutics peptide hormone phospholipase C epsilon pituitary adenylate cyclase activating polypeptide pituitary adenylate cyclase-activating peptide receptor postsynaptic presynaptic receptor respiratory response sensor stressor synaptotagmin synaptotagmin VII tool

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.

抽象的 “战斗或飞行”的反应是指由A引发的生理和精神唤醒状态身体威胁，情绪激动的事件或代谢灾难。虽然对每个的精确反应压力源可能会有所不同，所有这些都具有交感神经系统激活的一些基本特征。肾上腺囊肿细胞是周围交感反应的核心作用。什么时候在压力期间激活，他们将骑兵鸡尾酒排放到上静脉中以进行循环整个身体。这些恐怖调节心脏，肺和代谢功能偏爱生存或在受到威胁时保持内部条件。肾上腺髓质的分泌是依赖于释放乙酰胆碱（ACH）和垂体的孕妇方案纤维的输入腺苷酸环化酶激活多肽（PACAP）到铬蛋白细胞上。仍然不太了解的是 ACH和PACAP调谐激素如何适应方案射击频率的范围与同情语气的变化有关。提出了三个具体目标来填补我们的空白了解压力响应途径。目的将检验总体假设突触前的示意图输入通过铬蛋白细胞中的不同接收器耦合途径翻译成动态调节骑马输出量。 AIM 1建立在最新的初步数据上，该数据显示第一次，在固定神经胶质蛋白细胞突触中，任何突触型（SYT）的作用。计划研究，使用原位切片电生理学将定义Ca2+传感在此突触中的作用，并评估该想法由SYT7调节的突触设施，放大器的激素从铬蛋白细胞中排出固定纤维以高频排出。 AIM 2是由初步数据激励的将PACAP刺激转换为CA2+信号所必需的磷脂酶C- EPSILON（PLC）引起胞吐作用的细胞。 PACAP被认为是压力期间铬蛋白细胞分泌的基础。这就是促使我们将生产设施的固定型射击频率增加，plc活动的频率提高必须“打开”铬蛋白细胞以维持激素输出的增加。 AIM 3建立在显示的数据上 PACAP刺激铬蛋白细胞中的胞吐作用，但在矛盾地限制释放的同时进行包装在铬蛋白颗粒中的肽激素。与生物基因的差异释放有关胺和辣椒，我们将表征PACAP刺激的融合孔和研究它们受约束的机制。我们预计这些研究将提供连贯的分子和物理框架，用于了解突触前活动，突触后受体如何耦合的信号通路和胞吐作用是机械连接的，以调节应力反应。

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：
Proceedings of the National Academy of Sciences of the United States of America
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。