Metabolic regulation via intramitochondrial sAC

通过线粒体内 sAC 进行代谢调节

• 批准号: 8695560
• 负责人: JOCHEN BUCK
• 金额: $ 37.8万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-15 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8695560
• 关键词: ATP Synthesis Pathway; Ablation; Acute; Adenylate Cyclase; Affect; Animals; Astrocytes; Bicarbonates; Biochemical; Bioenergetics; Brain; Calcium; Carbon Dioxide; Catechol Estrogens; Cell membrane; Cells; Chronic; Cilia; Citric Acid Cycle; Communication; Complex; Cues; Cultured Cells; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cytoplasm; Data; Defect; Dependence; Diabetes Mellitus; Electron Transport; Electrons; Embryo; Enzymes; Epididymis; Equilibrium; Exhibits; Eye; Fertility; Fibroblasts; Frequencies; Functional disorder; Glucose; Glucose tolerance test; Health; Heterotrimeric GTP-Binding Proteins; Homeostasis; Hormones; Insulin; KRP protein; Kidney; Link; Mediating; Metabolic; Metabolic Diseases; Metabolic stress; Metabolism; Mitochondria; Mus; NADH; Neurons; Neurotransmitters; Nutrient; Nutritive Value; Oxidative Phosphorylation; Pancreas; Pathway interactions; Phenotype; Physiologic Intraocular Pressure; Physiological; Positioning Attribute; Production; Protons; Reactive Oxygen Species; Regulation; Relative (related person); Resources; Role; Second Messenger Systems; Signal Pathway; Signal Transduction; Source; System; Tissues; airway epithelium; blood glucose regulation; carbonate dehydratase; cell motility; detection of nutrient; electron donor; extracellular; feeding; glucose metabolism; glucose sensor; in vivo; inhibitor/antagonist; male; oxidative damage; respiratory; response; second messenger; sensor; sperm cell; wasting

DESCRIPTION (provided by applicant): It has become widely accepted that cAMP acts locally, in independently regulated signaling microdomains. Soluble adenylyl cyclase (sAC) is molecularly, biochemically and functionally distinct from the other known mammalian sources of cAMP, the transmembrane adenylyl cyclases (tmACs). While tmACs are positioned at the plasma membrane where they are regulated by heterotrimeric G proteins in response to extracellular cues such as hormones and neurotransmitters, sAC is distributed throughout the cytoplasm and in intracellular compartments, including mitochondria, where it is poised to provide the second messenger regulating the intracellular and intra-organellar targets of cAMP. Inside mitochondria, sAC-generated cAMP regulates components of the electron transport chain (ETC), increasing electron flux and the overall rate of ATP synthesis. This intramitochondrial sAC-cAMP signaling pathway linking cellular nutrient utilization with energy production defines a mechanism of short-term modulation of oxidative phosphorylation which allows the cell's respiratory machinery to respond to transient changes in nutritional availability, environmental conditions, and energy requirements. In this application, we propose to elucidate the physiological significance of this pathway. We propose to (1) determine the consequences of both chronic and acute abrogation of the intramitochondrial sAC-cAMP pathway in cultured cells using pharmacological inhibitors and cells derived from sAC-C1 KO mice; and (2) discern which of the known metabolic phenotypes seen in sAC-C1 KO mice are caused by abrogation of the intramitochondrial sAC-cAMP pathway. Understanding the role of this pathway is likely to have important implications for cell intrinsic nutrient sensing, diabetes, and metabolism in general, and it will reveal the functional significance of this intracellular cAMP microdomain.

描述（由申请人提供）：已被广泛接受的是，在独立调节的信号微域中，camp在本地行动。可溶性腺苷酸环化酶（SAC）在分子上，生化和功能上与其他已知的cAMP的哺乳动物来源，跨膜腺苷酸酯酶（TMAC）。虽然TMAC位于质膜上，在该质膜上，它们受到响应于细胞外线索（例如激素和神经递质）的响应，在整个细胞质和细胞内的细胞内分布中，SAC分布在包括线粒体的细胞内隔室，包括隔室的内部范围内，并在该隔离范围内进行了启动。在线粒体内部，SAC生成的cAMP调节电子传输链（ETC）的组件，增加电子通量和ATP合成的总体速率。这种室内囊囊信号信号通路将细胞营养利用与能量产生联系起来，定义了一种短期调节氧化磷酸化的机制，这使细胞的呼吸机械能够响应营养可用性，环境条件和能量需求的短暂变化。在此应用中，我们建议阐明该途径的生理意义。我们建议（1）使用源自SAC-C1 KO小鼠的药理学抑制剂和细胞来确定培养细胞中属性细胞中慢性和急性废除慢性和急性废除的后果； （2）辨别在SAC-C1 KO小鼠中看到的哪些已知代谢表型是由Intochrial sac-camp途径的废除引起的。了解该途径的作用可能对细胞内在的营养感应，糖尿病和代谢具有重要意义，并且它将揭示该细胞内cAMP微域的功能意义。