Oscillations in K(ATP) conductance drive slow calcium oscillations in pancreatic β-cells
Oscillations in K(ATP) conductance drive slow calcium oscillations in pancreatic β-cells
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K(ATP) 电导的振荡驱动胰腺 β 细胞中缓慢的钙振荡
DOI：
10.1016/j.bpj.2022.03.015
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发表时间：
2022
影响因子：
3.4
通讯作者：
Bertram, Richard
中科院分区：
文献类型：
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作者：
Marinelli, Isabella;Thompson, Benjamin M.;Parekh, Vishal S.;Fletcher, Patrick A.;Gerardo-Giorda, Luca;Sherman, Arthur S.;Satin, Leslie S.;Bertram, Richard
1984年，在胰岛β细胞中首次报道了ATP敏感性K+（K（ATP））通道，并且很快确定它们是将血糖水平转换为细胞电活动并因此转换为胰岛素分泌的主要手段。然而，K（ATP）通道在驱动胰岛β细胞的爆发性电活动（其驱动脉动胰岛素分泌）中所起的作用仍不清楚。一个困难是，当几种不同的离子通道类型被阻断时，爆发被消除，这使得区分因果关系和相关性变得很有挑战性。在这里，我们展示了一种方法，用于确定K（ATP）电导的活性依赖性振荡是否在驱动β细胞中的电爆发中发挥主要作用。我们使用数学模型来预测，如果K（ATP）是驱动因素，那么与直觉相反，ATP/ADP的平均值、峰值和最低值水平应该在支持爆发的浓度范围内对葡萄糖的变化保持不变。我们使用Perceval-HR在胰岛中测试这一点，以成像ATP/ADP中的振荡。我们发现，平均值，峰值和最低点水平确实是近似不变的，支持的假设，在K（ATP）电导振荡的主要驱动程序的缓慢爆发振荡通常在小鼠胰岛刺激葡萄糖水平。总之，我们提供的第一次，我们的知识，因果关系的证据，K（ATP）通道的作用，不仅作为葡萄糖调节的主要目标，但也为他们的作用，驱动爆发电活动和脉动胰岛素分泌。
ATP-sensitive K+(K(ATP)) channels were first reported in theβ-cells of pancreatic islets in 1984, and it was soon established that they are the primary means by which the blood glucose level is transduced to cellular electrical activity and consequently insulin secretion. However, the role that the K(ATP) channels play in driving the bursting electrical activity of isletβ-cells, which drives pulsatile insulin secretion, remains unclear. One difficulty is that bursting is abolished when several different ion channel types are blocked pharmacologically or genetically, making it challenging to distinguish causation from correlation. Here, we demonstrate a means for determining whether activity-dependent oscillations in K(ATP) conductance play the primary role in driving electrical bursting inβ-cells. We use mathematical models to predict that if K(ATP) is the driver, then contrary to intuition, the mean, peak, and nadir levels of ATP/ADP should be invariant to changes in glucose within the concentration range that supports bursting. We test this in islets using Perceval-HR to image oscillations in ATP/ADP. We find that mean, peak, and nadir levels are indeed approximately invariant, supporting the hypothesis that oscillations in K(ATP) conductance are the main drivers of the slow bursting oscillations typically seen at stimulatory glucose levels in mouse islets. In conclusion, we provide, for the first time to our knowledge, causal evidence for the role of K(ATP) channels not only as the primary target for glucose regulation but also for their role in driving bursting electrical activity and pulsatile insulin secretion.