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是一个重要的第二使者，可调节心脏中的几个生理事件，包括收缩，代谢和基因转录。最近的一些研究不仅说明了磷酸二酯酶（PDE）对控制心脏基底cAMP水平的重要性，而且还在调节由于PDE的细胞位置而调节cAMP的局部变化。因此，确定管理PDE定位和活性的分子决定因素，以及归因于每个PDE的生物学过程，将进一步了解我们对心脏中cAMP信号的了解。我们先前已经描述了一种脚手架蛋白，该蛋白质将磷酸二酯酶PDE4D3隔离为分化心肌细胞中的核膜。 A-激酶锚固蛋白MAKAP保持了一个由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ryanonodine受体组成的复合物。先前的数据表明，Makap精心策划了PDE4D3的ERK5和PKA调节。这些磷酸化引起的PDE4D3活性的变化反过来会调节复合物周围的营地浓度，最终调节复合物中的所有营地效应子，即PKA，PDE4D3和EPAC。该提案的三个具体目的将尝试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磷酸化的功能后果PDE的去磷酸化。心脏病是美国死亡的第一大原因。心脏肥大是心脏对心脏产量的持续需求反应的主要补偿机制。最终，心脏肥大会导致心脏病和心力衰竭发展。然而，一些研究表明，抑制心脏肥大会降低死亡和发展为心力衰竭的风险。这项研究将进一步了解心脏肥大的分子机制，并有助于确定药物设计的新靶标，以帮助治疗肥大。