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
• 负责人: Arun Anantharam
• 金额: $ 37.02万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10609941
• 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; Circulation; Coupled; Cyclic AMP; Cytoplasmic Granules; Data; Dynamin; Electrophysiology (science); Emotional; Event; Exocytosis; Fiber; Frequencies; G-Protein-Coupled Receptors; Guanosine Triphosphate Phosphohydrolases; Hormone secretion; Hormones; Human; Hypoglycemia; Image; In Situ; In Vitro; Injury; Laboratories; Link; Lung; Measures; Mental Health; Metabolic; Modality; Molecular; Neurons; Neurotransmitters; Output; Pathway interactions; Peptides; Perfusion; 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 Receptors; 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; pharmacologic; phospholipase C epsilon; pituitary adenylate cyclase activating polypeptide; postsynaptic; presynaptic; receptor; respiratory; response; seal; sensor; stressor; synaptotagmin; synaptotagmin VII; tool

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 “战斗或逃跑”反应是指由某种刺激引发的生理和精神高度兴奋的状态。 身体威胁、情绪激动的事件或代谢紊乱。尽管对每一项的反应都十分精确 压力源可能有所不同，但都具有交感神经系统激活的一些基本特征。 肾上腺髓质嗜铬细胞是外周交感神经反应的核心效应器。什么时候 在压力期间被激活，它们将多种激素释放到肾上腺静脉中进行循环 遍布全身。这些激素通过以下方式调节心脏、肺和代谢功能： 当他们受到威胁时有利于生存或维持内部条件。肾上腺髓质的分泌物是 依赖于节前内脏纤维的输入，释放乙酰胆碱 (ACh) 和垂体 将腺苷酸环化酶激活多肽 (PACAP) 附着到嗜铬细胞上。仍然知之甚少的是 ACh 和 PACAP 如何调节激素释放以适应内脏放电频率范围 与交感神经张力的变化有关。提出了三个具体目标来填补我们的这一空白 了解应激反应途径。目标将检验总体假设，即变化 突触前内脏输入通过嗜铬细胞中不同的受体偶联途径转化为 动态调节激素输出量。目标 1 建立在最近的初步数据的基础上，该数据显示， 第一次，任何突触结合蛋白（Syt）在内脏嗜铬细胞突触中发挥作用。计划的学习， 使用原位切片电生理学，将定义 Ca2+ 传感在此突触的作用，并评估该想法 受 Syt7 调节的突触促进会在以下情况下放大嗜铬细胞的激素释放： 内脏纤维以高频放电。目标 2 的动机是初步数据显示 将 PACAP 刺激转变成嗜铬细胞中的 Ca2+ 信号需要磷脂酶 C-epsilon (PLC) 引起胞吐作用的细胞。 PACAP 被认为是应激期间嗜铬细胞分泌的基础。这有 促使我们推测，随着内脏放电频率的增加，产生促进作用，PLC 活动 嗜铬细胞必须“开启”以维持激素输出的增加。目标 3 建立在数据之上，数据显示 PACAP 刺激嗜铬细胞的胞吐作用，但同时又限制了 包装在嗜铬颗粒内的肽激素。与生物源的差异释放相关 胺和激素肽，我们将表征 PACAP 刺激的融合孔的特性和 研究限制它们的机制。我们期望这些研究能够提供一个连贯的 用于理解突触前活动、突触后受体如何进行的分子和生理框架 耦合信号通路和胞吐作用在机制上与调节应激反应有关。