CaMKII signaling in insulin secretion and response

胰岛素分泌和反应中的 CaMKII 信号传导

基本信息

批准号：
7229963
负责人：
K. Ulrich Bayer
金额：
$ 14.92万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-02-01 至 2009-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7229963
关键词：
Affect Agonist Beta Cell Biochemical Brain Cell Line Cells Chelating Agents Complex D Cells Detection Diabetes Mellitus Epidemic Failure Fatty Acids Future Generations Glucose Glutamate Receptor Glutamates Goals Hippocampus (Brain)Insulin Islet Cell Islets of Langerhans Libraries Mediating Mediator of activation protein Methods N-Methyl-D-Aspartate Receptors N-Methylaspartate NR1 NMDA receptor Neurons Neurotransmitters Nutrient Pancreas Pathway interactions Pattern Peptides Phosphotransferases Property Protein Isoforms Protein Overexpression Proteins RNA Interference RNA Splicing Regulation Reverse Transcriptase Polymerase Chain Reaction Role Signal Transduction Signaling Molecule Staining method Stains Structure of beta Cell of islet Testing Transfection Variant Viral Vector alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid amino 3 hydroxy 5 methylisoxazole 4 propionate base blood glucose regulation calmodulin-dependent protein kinase II cell type gain of function improved inhibitor/antagonist insulin secretion islet knock-down mutant novel novel therapeutics protein protein interaction receptor function research study response voltage

项目摘要

DESCRIPTION (provided by applicant): The level of secreted insulin determines whether nutrients are metabolized for storage, or storage complexes are broken down for generation of energy. Failure to produce insulin -or to properly respond to it- results in diabetes, an illness of epidemic proportions in the US. Insulin is secreted from pancreatic Langerhans' islets in response to high levels of glucose, further potentiated by fatty acids. This requires a rise in intracellular Ca2+ concentration, generated by L-type voltage dependent Ca2+ channels (VDCC). Insulin secretion from beta cells is modulated by signals released from A and D cells, and recent evidence suggests that this may also involve signaling mediated by glutamate, the major excitatory neurotransmitter in brain. Activation of neuronal NMDA- and AMPA-type glutamate receptors leads to Ca2+ influx (directly or via VDCC activation), and thus may contribute to Ca2+ signals also in islet cells. The Ca2+/calmodulin dependent protein kinase II (CaMKII) is established as a key mediator of neuronal Ca2+ signals. CaMKII may also be required for insulin secretion, however, this is largely based on experiments that used inhibitors which also affect other kinases as well as VDCCs. Currently, even the expression of CaMKII isoforms and glutamate-receptor types in Langerhans' islets and their distribution among the different cell types is unclear or controversial. The CaMKII isoforms can differ in their subcellular targeting and their ability to interact with other proteins (including NMDA receptors and possibly VDCCs). The subunit composition of ionotropic glutamate receptors determines channel properties (including Ca2+ conductance) and regulation of targeting. The CaMKII isoform and glutamate receptor subunit composition would thus affect the connection with other signaling molecules and pathways. Our ultimate goal is to determine if and how CaMKII, VDCCs, and glutamate receptors function together in the regulation of nutrient-induced insulin secretion from pancreatic beta cells. Understanding the mechanisms of insulin secretion regulation will allow to devise new therapeutic avenues for treatment of diabetes. In this proposal we will: (1) Determine expression pattern of CaMKII and glutamate receptor isoforms among islet cells. (2) Determine regulation of insulin secretion by CaMKII in isolated islets and in beta cell lines. (3) Test feasibility of methods to study function of specific CaMKII isoforms in beta cells and islets.

描述（由申请人提供）：分泌的胰岛素水平决定了营养物质是否被代谢以进行储存，或者储存复合物是否被分解以产生能量。无法产生胰岛素或无法对其做出适当反应会导致糖尿病，这是一种在美国流行的疾病。胰岛素是由胰岛分泌的，以响应高水平的葡萄糖，并进一步受到脂肪酸的增强。这需要增加由 L 型电压依赖性 Ca2+ 通道 (VDCC) 产生的细胞内 Ca2+ 浓度。 β 细胞的胰岛素分泌受到 A 细胞和 D 细胞释放的信号的调节，最近的证据表明，这可能还涉及谷氨酸（大脑中主要的兴奋性神经递质）介导的信号传导。神经元 NMDA 和 AMPA 型谷氨酸受体的激活导致 Ca2+ 流入（直接或通过 VDCC 激活），因此也可能在胰岛细胞中产生 Ca2+ 信号。 Ca2+/钙调蛋白依赖性蛋白激酶 II (CaMKII) 被确定为神经元 Ca2+ 信号的关键介质。 CaMKII 也可能是胰岛素分泌所必需的，然而，这主要基于使用抑制剂的实验，这些抑制剂也影响其他激酶以及 VDCC。目前，甚至朗格汉斯胰岛中 CaMKII 亚型和谷氨酸受体类型的表达及其在不同细胞类型中的分布也不清楚或存在争议。 CaMKII 亚型的亚细胞靶向性以及与其他蛋白质（包括 NMDA 受体和可能的 VDCC）相互作用的能力可能有所不同。离子型谷氨酸受体的亚基组成决定通道特性（包括 Ca2+ 电导）和靶向调节。因此，CaMKII 亚型和谷氨酸受体亚基组成会影响与其他信号分子和途径的连接。我们的最终目标是确定 CaMKII、VDCC 和谷氨酸受体是否以及如何在调节营养诱导的胰腺 β 细胞胰岛素分泌中共同发挥作用。了解胰岛素分泌调节机制将有助于设计出治疗糖尿病的新治疗途径。在本提案中，我们将：（1）确定胰岛细胞中 CaMKII 和谷氨酸受体亚型的表达模式。 (2) 确定 CaMKII 在分离的胰岛和 β 细胞系中对胰岛素分泌的调节。 (3) 测试研究 β 细胞和胰岛中特定 CaMKII 亚型功能的方法的可行性。