Regulation of Adenylyl Cyclase Signaling Pathways

腺苷酸环化酶信号通路的调节

基本信息

批准号：
10689698
负责人：
Carmen W. Dessauer
金额：
$ 41.34万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10689698
关键词：
A kinase anchoring protein Address Adenylate Cyclase Adrenergic beta-Antagonists Agonist Anxiety Asthma Automobile Driving Behavior Cardiac Cardiac Myocytes Cause of Death Centers for Disease Control and Prevention (U.S.)Clinical Complex Cyclic AMP Drug Addiction Drug Targeting Environment Enzymes Event Funding G-Protein-Coupled Receptors GTP-Binding Protein alpha Subunits, Gs GTP-Binding Proteins Heart Abnormalities Heart Diseases Heart Rate Immune response Learning Macromolecular Complexes Memory Modification Motor Names National Institute of General Medical Sciences Nature Opioid Pain Physiological Physiological Processes Process Production Property Proteins Regulation Renal function Research Signal Pathway Signal Transduction Site Specificity Stress System Therapeutic Intervention Tissues biological systems body system career cell growth regulation drug withdrawal functional outcomes heart function heart rhythm interest novel novel therapeutic intervention response scaffold small molecule tool transmission process

项目摘要

Summary Adenylyl cyclase (AC) and its product, cyclic AMP, regulate functional outcomes in every mammalian tissue and organ system, controlling processes such as learning and memory, motor coordination, cardiac contractility, drug dependency and withdrawal, renal function, pain, stress, immune responses, and anxiety behavior, to name just a few. Importantly, G protein coupled receptors that transmit signals via stimulation (Gαs) or inhibition (Gαi) of AC are major clinical drug targets (e.g. beta-blockers for heart disease, opioids for pain, or beta-agonists for asthma). Funded largely by NIGMS, my research career over the last 27 years has focused on how the catalytic activity of AC enzymes are regulated by G proteins and other regulatory molecules. Additionally, we are interested in how AC/cAMP signaling specificity can occur in a cellular environment. We have identified multiple macromolecular complexes assembled by A-kinase anchoring proteins that respond to low levels of local cAMP production upon anchoring of AC to the system, driving physiological responses, or when altered, have pathophysiological consequences. However, many fundamental questions remain about the mechanisms of AC regulation within these signalosomes, the regulation of ACs by covalent modifications, and the potential for regulation of cellular events from intracellular sites. To address these key questions, we have performed proximity dependent identification of near neighbors (BioID) to build a comprehensive AC interaction network in cardiomyocytes and characterized new tools for selectively probing the properties of AC9. These will be applied to broad projects that examine the scaffolding of AC activity that ultimately control cardiac pacemaking and conduction. Popdc proteins act as one novel scaffold for AC enzymes that promote AC activity within the complex to drive cAMP-dependent regulation of TREK channels. The unique mechanism of AC regulation by Popdc and the localization of this complex will be further explored in two related projects. Additionally, we will examine the mechanism of AC regulation by a novel modifying enzyme, identified by BioID. Although these modes of regulating cAMP signaling will be examined in the context of cardiomyocytes and cardiac function, many of the mechanisms are universal in nature and have implications for many biological systems.

概括腺苷酸环化酶 (AC) 及其产物环 AMP 可调节每个哺乳动物组织的功能结果和器官系统，控制学习和记忆、运动协调、心脏等过程收缩力、药物依赖性和戒断、肾功能、疼痛、压力、免疫反应和焦虑举几个例子，重要的是，G 蛋白偶联受体通过刺激传递信号。 AC 的 (Gαs) 或抑制 (Gαi) 是主要的临床药物靶点（例如治疗心脏病的β受体阻滞剂、治疗心脏病的阿片类药物）我的研究生涯主要由 NIGMS 资助，过去 27 年重点研究 AC 酶的催化活性如何受到 G 蛋白和其他调控因子的调节此外，我们对 AC/cAMP 信号传导特异性如何在细胞中发生感兴趣。我们已经鉴定出由 A-激酶锚定组装的多个大分子复合物。在 AC 锚定到系统后，对局部 cAMP 产生的低水平做出反应的蛋白质，驱动生理反应或何时产生病理生理学后果。关于这些信号体中 AC 调节机制的基本问题仍然存在，通过共价修饰调节 AC，以及细胞内调节细胞事件的潜力为了解决这些关键问题，我们对邻近站点进行了邻近性相关识别。（BioID）在心肌细胞中建立一个全面的 AC 相互作用网络，并表征了新工具选择性地探索 AC9 的特性，这些将应用于检查脚手架的广泛项目。最终控制心脏起搏和传导的 AC 活性的 Popdc 蛋白是一种新型蛋白。 AC 酶的支架，可促进复合物内的 AC 活性，从而驱动 cAMP 依赖性调节 TREK 通道。 Popdc 的 AC 调节独特机制以及该复合物的本地化将是此外，我们将在两个相关项目中进一步探讨AC调节机制。 BioID 鉴定出新的修饰酶，尽管这些调节 cAMP 信号传导的模式将受到限制。在心肌细胞和心脏功能的背景下进行检查，许多机制在自然并对许多生物系统产生影响。