Calcium-activated and voltage-gated potassium channels of the pancreatic islet impart distinct and complementary roles during secretagogue induced electrical responses
Calcium-activated and voltage-gated potassium channels of the pancreatic islet impart distinct and complementary roles during secretagogue induced electrical responses
复制标题
DOI：
10.1113/jphysiol.2010.190207
复制
发表时间：
2010-09-15
影响因子：
5.5
通讯作者：
Philipson, Louis H.
中科院分区：
文献类型：
--
作者：
Jacobson, David A.;Mendez, Felipe;Philipson, Louis H.
葡萄糖诱导的β细胞动作电位（AP）复极化由钾流出通过电压门控（Kv）和钙激活（K-Ca）钾通道调节。因此，β细胞的初级Kv通道Kv2.1的消融导致AP持续时间增加。然而，Kv2.1-/-胰岛电活动仍然对钾通道抑制剂四乙铵敏感。因此，我们利用Kv2.1-/-胰岛来表征Kv和K-Ca通道及其各自在调节β细胞AP中的作用。5 μ m CP 339818可抑制Kv2.1-/-β细胞中存在的剩余Kv电流。抑制Kv2.1-/-小鼠β细胞中的剩余Kv电流使AP放电频率增加39.6%，但没有显著增强葡萄糖刺激的胰岛素分泌（GSIS）。CP 339818对胰岛AP频率的适度调节暗示其他K+通道（可能是K-Ca通道）也参与调节AP复极化。用slotoxin阻断K-Ca通道BK使β细胞AP振幅增加28.2%，而用异海松酸激活BK通道使β细胞AP振幅降低30.6%。有趣的是，K-Ca通道SK显著促进Kv2.1-/-小鼠胰岛AP复极化。只有当Kv2.1被消融或抑制并增强GSIS 2.7倍时，SK通道的抑制才使AP放电频率降低66%，AP持续时间增加67%。人类胰岛也表达SK 3通道，其β细胞AP频率在apamin下显著增加4.8倍。这些结果揭示了Kv和K-Ca通道的重要复极化作用，并确定了SK通道活性在调节钙与钠依赖性AP放电中的不同作用。
Glucose-induced beta-cell action potential (AP) repolarization is regulated by potassium efflux through voltage gated (Kv) and calcium activated (K-Ca) potassium channels. Thus, ablation of the primary Kv channel of the beta-cell, Kv2.1, causes increased AP duration. However, Kv2.1-/- islet electrical activity still remains sensitive to the potassium channel inhibitor tetraethylammonium. Therefore, we utilized Kv2.1-/- islets to characterize Kv and K-Ca channels and their respective roles in modulating the beta-cell AP. The remaining Kv current present in Kv2.1-/- beta-cells is inhibited with 5 mu m CP 339818. Inhibition of the remaining Kv current in Kv2.1-/- mouse beta-cells increased AP firing frequency by 39.6% but did not significantly enhance glucose stimulated insulin secretion (GSIS). The modest regulation of islet AP frequency by CP 339818 implicates other K+ channels, possibly K-Ca channels, in regulating AP repolarization. Blockade of the K-Ca channel BK with slotoxin increased beta-cell AP amplitude by 28.2%, whereas activation of BK channels with isopimaric acid decreased beta-cell AP amplitude by 30.6%. Interestingly, the K-Ca channel SK significantly contributes to Kv2.1-/- mouse islet AP repolarization. Inhibition of SK channels decreased AP firing frequency by 66% and increased AP duration by 67% only when Kv2.1 is ablated or inhibited and enhanced GSIS by 2.7-fold. Human islets also express SK3 channels and their beta-cell AP frequency is significantly accelerated by 4.8-fold with apamin. These results uncover important repolarizing roles for both Kv and K-Ca channels and identify distinct roles for SK channel activity in regulating calcium- versus sodium-dependent AP firing.