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）：分泌的胰岛素水平确定营养素是否被代谢以存储，或者分解储存络合物以生成能量。未能产生胰岛素 - 或适当地应对糖尿病，这是美国流行病的疾病。胰岛素是从胰腺兰加尔人的胰岛中分泌的，响应高葡萄糖，进一步由脂肪酸增强。这需要由L型电压依赖性Ca2+通道（VDCC）产生的细胞内Ca2+浓度上升。 β细胞中的胰岛素分泌受到A和D细胞释放的信号的调节，最近的证据表明，这也可能涉及由谷氨酸介导的信号传导，谷氨酸介导，这是大脑中主要的兴奋性神经递质。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），因此在胰岛细胞中也可能有助于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+信号的关键介体。胰岛素分泌也可能需要CAMKII，但是，这主要基于使用抑制剂，这些抑制剂也影响了其他激酶以及VDCC。目前，即使是Langerhans胰岛中CaMKII同工型和谷氨酸蛋白酶受体类型的表达，它们在不同细胞类型中的分布也不清楚或有争议。 CAMKII同工型的亚细胞靶向和与其他蛋白质相互作用的能力（包括NMDA受体和可能的VDCC）可能有所不同。离子谷氨酸受体的亚基组成决定了通道特性（包括Ca2+电导）和靶向的调节。因此，CAMKII同工型和谷氨酸受体亚基组成将影响与其他信号分子和途径的联系。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胰腺β细胞中营养诱导的胰岛素分泌方面起作用。了解胰岛素分泌调节的机制将允许设计新的治疗途径来治疗糖尿病。在此提案中，我们将：（1）确定胰岛细胞中CAMKII和谷氨酸受体同工型的表达模式。（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）测试方法研究特定CAMKII同工型在β细胞和胰岛中的功能的可行性。