METABOLICALLY-COUPLED ION CHANNEL INTERACTIONS IN ISLETS

胰岛中代谢耦合离子通道相互作用

• 批准号: 2145618
• 负责人: LESLIE S. SATIN
• 金额: $ 14.02万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-12-01 至 1997-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2145618
• 关键词: calcium; calcium channel; calcium indicator; computer simulation; disease /disorder model; electrophysiology; glucose metabolism; intracellular; laboratory mouse; noninsulin dependent diabetes mellitus; pancreatic islet function; pancreatic islets; potassium channel; tissue /cell culture; voltage /patch clamp; voltage gated channel

Non-insulin-dependent diabetics have impaired glucose-dependent insulin secretion. Our general hypothesis is that abnormal islet beta-cell calcium channel activity is an intrinsic lesion that contributes to this secretory impairment. In normal islets, a rise in plasma glucose causes different beta-cell ion channels to interact to produce a characteristic pattern of membrane electrical activity called bursting. Bursting consists of cycles of rapid voltage spiking superimposed on slow depolaring voltage plateaus. Both the spikes and the plateaus are dependent on Ca channel activity and mediated the Ca uptake necessary for insulin release. However, the role of Ca channels and other ion channels in normal burst production is unclear. Our working hypothesis is that bursting results from the periodic slow inhibition or inactivation of Ca channel activity by membrane depolarization (Ca Channel Hypothesis). Alternatively, Ca influx may lead to the cyclic activation of Ca- activated potassium (K) channels (KCa Hypothesis) or ATP-sensitive K channels (Ca-KATP Hypothesis). The coupling between cell fuel metabolism and electrical activity is hypothesized to result from metabolite modulation of Ca and KATP channel activity. The feasibility of our diabetes hypothesis will be tested by determining whether abnormal Ca channel activity is a primary lesion in the db/db diabetic mouse model and can produce abnormal electrical activity and secretion by altering intracellular free [Ca]signalling. Ion channel recording techniques combined with a new type of experimental protocol, computer modelling of beta-cell electrical activity and intracellular free [Ca] measurements will be used to test these hypotheses in normal and diabetic mouse beta- cells.

非胰岛素依赖型糖尿病患者的葡萄糖依赖性胰岛素受损 分泌物 我们的假设是异常的胰岛β细胞 钙通道活性是一种内在的损伤， 分泌障碍 在正常胰岛中，血糖升高会导致 不同的β细胞离子通道相互作用， 膜电活动的模式称为爆发。 爆破 由快速电压尖峰叠加在缓慢电压尖峰上的周期组成， 去极化电压平台。 尖峰和高原都是 依赖于钙通道的活动，并介导钙摄取所必需的 胰岛素释放 然而，Ca通道和其他离子通道的作用 在正常的突发生产是不清楚的。 我们的假设是 爆发是由钙离子周期性缓慢抑制或失活引起的 钙离子通道活性通过膜去极化（钙通道假说）。 或者，Ca内流可能导致Ca-2+的循环激活。 激活的钾（K）通道（KCa假说）或ATP敏感的K Ca-KATP通道假说（Ca-KATP Hypothesis） 细胞燃料代谢之间的耦合 而电活动被假设是由代谢产物 调节Ca和KATP通道活性。 我们的可行性 糖尿病假说将通过确定是否异常钙 通道活性是db/db糖尿病小鼠模型中的主要损害 并能通过改变 细胞内游离[Ca]信号传导。 离子通道记录技术 结合一种新型的实验方案， β细胞电活动和细胞内游离[Ca]测量 将用于测试这些假设在正常和糖尿病小鼠β- 细胞