Regulation of Adenylyl Cyclase Signaling Pathways

腺苷酸环化酶信号通路的调节

• 批准号: 10405311
• 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
• 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/10405311
• 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

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）及其产物环状AMP调节每个哺乳动物组织中的功能结果 和器官系统，控制学习和记忆等过程，运动协调，心脏 收缩力，药物依赖和戒断，肾功能，疼痛，压力，免疫调查和动画 行为，仅举几例。重要的是，G蛋白偶联受体通过刺激传输信号 AC的（GαS）或抑制（GαI）是主要的临床药物靶标（例如，心脏病的β受体阻滞剂，阿片类药物的阿片类药物 疼痛或哮喘的β-激动剂）。我过去27年中的研究生涯主要由Nigms资助 专注于AC酶的催化活性如何受G蛋白和其他调节性调节 分子。此外，我们对AC/CAMP信号特异性如何在细胞中发生感兴趣 环境。我们已经确定了由A-激酶锚定组装的多个大分子复合物 锚定AC锚定向系统后，对当地营地生产水平较低的蛋白质有反应，驾驶 身体反应或改变时会产生病理生理后果。但是，很多 关于这些信号体内AC调节机制的基本问题仍然是 通过共价修改调节ACS，并从细胞内调节细胞事件的潜力 站点。为了解决这些关键问题，我们已经对近邻居进行了靠近依赖性识别 （Bioil）在心肌细胞中建立一个综合的交流网络，并以新工具为特征 有选择地探索AC9的性质。这些将应用于检查脚手架的广泛项目 AC活性最终控制心脏起搏和传导。 PopDC蛋白充当一本小说 AC酶的脚手架，这些酶促进复合物内的AC活性以驱动cAMP依赖的调节 跋涉频道。 POPDC和该复合物的本地化的AC调节的独特机制将是 在两个相关项目中进一步探讨了。此外，我们将检查A AC调节的机理 新颖的修饰酶，由生物分子鉴定。尽管这些调节营地信号的模式将是 在心肌细胞和心脏功能的背景下检查，许多机制在 自然，对许多生物系统具有影响。