mAKAP-orchestrated phosphorylation events: regulation of PDE4D3

mAKAP 精心策划的磷酸化事件：PDE4D3 的调节

• 批准号: 7146633
• 负责人: Kimberly L Dodge-Kafka
• 金额: $ 36.04万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-10 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7146633
• 关键词: A kinase anchoring protein; binding sites; calcium channel; cyclic AMP; enzyme activity; guanine nucleotide exchange factors; immunoprecipitation; laboratory rat; mitogen activated protein kinase; phosphodiesterases; phosphoprotein phosphatase; phosphorylation; protein kinase A; ventricular hypertrophy

DESCRIPTION (provided by applicant): cAMP is an important second messenger that regulates several physiological events in the heart including contraction, metabolism and gene transcription. Several recent studies have illustrated not only the importance of phosphodiesterases (PDE) for the control of basal cAMP levels in the heart, but also in the regulation of localized changes of cAMP due to the cellular location of PDEs. Therefore, identifying the molecular determinants governing PDE localization and activity, as well as the biological processes attributed to each PDE, will further our knowledge of cAMP signaling in the heart. We have previously described a scaffolding protein that sequesters the phosphodiesterase PDE4D3 to the nuclear envelope in differentiated cardiac myocytes. The A-Kinase Anchoring Protein mAKAP maintains a complex consisting of the cAMP-dependent protein kinase, PDE4D3, the Map Kinase ERK5, the guanine nucleotide exchange factor Epac, the protein phosphatase 2A, and the Ryanodine Receptor. Previous data has shown mAKAP orchestrated both ERK5 and PKA regulation of PDE4D3. These phosphorylation-induced changes in PDE4D3 activity will in turn modulate the concentration of cAMP surrounding the complex, ultimately regulating all cAMP effectors in the complex, namely PKA, PDE4D3 and Epac. The three Specific Aims of this proposal will try to 1) elucidate the physiological events that regulate PDE4D3 phosphorylation regulate cAMP concentration and the phosphorylation state of the Ryanodine Receptor 2) determine the functional consequence of PDE4D3 phosphorylation on Epac-mediated ERK5 activity and ERK5-mediated cardiac hypertrophy, and 3) identify the phosphatase in the complex that governs dephosphorylation of the PDE. Heart disease is the number one cause of death in the United States. Cardiac hypertrophy is the major compensatory mechanism by which the heart responds to a continued, increased demand for cardiac output. Ultimately, cardiac hypertrophy leads to progression into cardiac disease and to heart failure. However, several studies have shown that inhibition of cardiac hypertrophy lowers the risk of death and progression into heart failure. This study will further our understanding of the molecular mechanism of cardiac hypertrophy and help to identify novel targets for drug design to aid in the treatment of hypertrophy.

描述（由申请人提供）：cAMP 是重要的第二信使，调节心脏中的多种生理事件，包括收缩、代谢和基因转录。最近的几项研究不仅说明了磷酸二酯酶 (PDE) 对于控制心脏中基础 cAMP 水平的重要性，而且还说明了由于 PDE 的细胞位置而导致的 cAMP 局部变化的调节。因此，确定控制 PDE 定位和活性的分子决定因素，以及每个 PDE 的生物过程，将进一步加深我们对心脏中 cAMP 信号传导的了解。我们之前描述了一种支架蛋白，它将磷酸二酯酶 PDE4D3 隔离到分化心肌细胞的核膜上。 A 激酶锚定蛋白 mAKAP 维持一个由 cAMP 依赖性蛋白激酶、PDE4D3、Map 激酶 ERK5、鸟嘌呤核苷酸交换因子 Epac、蛋白磷酸酶 2A 和 Ryanodine 受体组成的复合物。之前的数据显示 mAKAP 精心策划了 PDE4D3 的 ERK5 和 PKA 调节。这些磷酸化诱导的 PDE4D3 活性变化将反过来调节复合物周围的 cAMP 浓度，最终调节复合物中的所有 cAMP 效应子，即 PKA、PDE4D3 和 Epac。该提案的三个具体目标将尝试 1) 阐明调节 PDE4D3 磷酸化的生理事件，调节 cAMP 浓度和 Ryanodine 受体的磷酸化状态 2) 确定 PDE4D3 磷酸化对 Epac 介导的 ERK5 活性和 ERK5 介导的功能后果心脏肥大，3) 识别复合物中控制 PDE 去磷酸化的磷酸酶。心脏病是美国第一大死因。心脏肥大是心脏对心输出量持续增加的需求做出反应的主要代偿机制。最终，心脏肥大导致进展为心脏病和心力衰竭。然而，一些研究表明，抑制心脏肥大可以降低死亡和进展为心力衰竭的风险。这项研究将进一步加深我们对心脏肥大分子机制的理解，并有助于确定药物设计的新靶点，以帮助治疗肥厚。