Abstract：
Gain of function mutations in the pore forming Kir6 subunits of the ATP sensitive K+ channels (K(ATP) channels) of pancreatic β-cells are the major cause of neonatal diabetes in humans. In this study, we show that in insulin secreting mouse β-cell lines, gain of function mutations in Kir6.1 result in a significant connexin36 (Cx36) overexpression, which form gap junctional connections and mediate electrical coupling between β-cells within pancreatic islets. Using computational modeling, we show that upregulation in Cx36 might play a functional role in the impairment of glucose stimulated Ca2+ oscillations in a cluster of β-cells with Kir6.1 gain of function mutations in their K(ATP) channels (GoF-K(ATP) channels). Our results show that without an increase in Cx36 expression, a gain of function mutation in Kir6.1 might not be sufficient to diminish glucose stimulated Ca2+ oscillations in a β-cell cluster. We also show that a reduced Cx36 expression, which leads to loss of coordination in a wild-type β-cell cluster, restores coordinated Ca2+ oscillations in a β-cell cluster with GoF-K(ATP) channels. Our results indicate that in a heterogenous β-cell cluster with GoF-K(ATP) channels, there is an inverted u-shaped nonmonotonic relation between the cluster activity and Cx36 expression. These results show that in a neonatal diabetic β-cell model, gain of function mutations in the Kir6.1 cause Cx36 overexpression, which aggravates the impairment of glucose stimulated Ca2+ oscillations.
摘要：
胰腺β细胞的ATP敏感性K通道（K（ATP）通道）的孔形成Kir6亚基中的功能突变增益是人类新生儿糖尿病的主要原因。在这项研究中,我们表明在分泌胰岛素的小鼠β细胞系中，Kir6.1中的功能增益突变导致显著的连接蛋白36（Cx36）过表达，它们形成缝隙连接并介导胰岛内β细胞之间的电耦合。使用计算建模，我们表明，Cx36的上调可能在β细胞簇的葡萄糖刺激的Ca2振荡的损害中起功能作用，其K（ATP）通道（GoF-K（ATP）通道）具有Kir6.1功能获得突变。我们的结果表明，Cx36表达没有增加，Kir6.1中的功能增加突变可能不足以减少β细胞簇中葡萄糖刺激的Ca2振荡。我们还显示Cx36表达减少，导致野生型β细胞簇失去协调，通过GoF-K（ATP）通道恢复β细胞簇中协调的Ca2振荡。我们的结果表明，在具有GoF-K（ATP）通道的异质β细胞簇中，簇活性与Cx36表达之间存在倒u形非单调关系。这些结果表明，在新生儿糖尿病β细胞模型中，Kir6.1中的功能增益突变导致Cx36过表达，这加剧了葡萄糖刺激的Ca2振荡的损害。
