BK channels mediate a novel ionic mechanism that regulates glucose-dependent electrical activity and insulin secretion in mouse pancreatic β-cells
BK channels mediate a novel ionic mechanism that regulates glucose-dependent electrical activity and insulin secretion in mouse pancreatic β-cells
复制标题
DOI：
10.1113/jphysiol.2009.184341
复制
发表时间：
2010-09-15
影响因子：
5.5
通讯作者：
Satin, Leslie S.
中科院分区：
文献类型：
--
作者：
Houamed, Khaled M.;Sweet, Ian R.;Satin, Leslie S.
BK通道是由细胞内钙离子和膜去极化共同激活的大的单一电导K+通道。我们发现BK通道调节葡萄糖升高的小鼠胰岛β细胞的电活动。在11.1 mm葡萄糖中，非肽基BK通道阻滞剂paxilline将β细胞动作电位（APs）的高度增加了21 mV，而不影响爆发期或沉默期的持续时间。在离体β细胞中，paxilline使AP高度增加16 mV，而不影响静息膜电位。在电压箝位中，paxilline阻断了由短去极化激活的向外电流的瞬态组分，该组分至少占初始向外K+电流的90%。这种BK电流（I-BK）被Ca2+通道阻滞剂Cd2+ (200 μ m)或尼莫地平（1 μ m）阻断，并被FPL-64176 （1 μ m）增强。BK通道阻断剂iberiotoxin （100 nm）对I-BK也有56%的阻断作用。在生理电压范围内，I-BK的激活速度比延迟整流器I-Kv快10倍以上，并且部分失活。类似AP的命令显示，I-BK的激活和失活速度比I-Kv快，占I-K峰值的86%，这解释了为什么I-BK块增加了AP高度。在11.1 mm葡萄糖加paxilline中记录的AP上，一个更高振幅的AP样命令，激活了4倍的I-Kv，并显着增加了Ca2+的进入。Paxilline使11.1 mm葡萄糖下的胰岛胰岛素分泌增加67%，但对2.8 mm葡萄糖下的胰岛胰岛素分泌没有影响。这些数据表明了一种改进的β细胞AP生成模型，其中I-BK和I-Kv协调AP复极。
BK channels are large unitary conductance K+ channels cooperatively activated by intracellular calcium and membrane depolarisation. We show that BK channels regulate electrical activity in beta-cells of mouse pancreatic islets exposed to elevated glucose. In 11.1 mm glucose, the non-peptidyl BK channel blocker paxilline increased the height of beta-cell action potentials (APs) by 21 mV without affecting burst- or silent-period durations. In isolated beta-cells, paxilline increased AP height by 16 mV without affecting resting membrane potential. In voltage clamp, paxilline blocked a transient component of outward current activated by a short depolarisation, which accounted for at least 90% of the initial outward K+ current. This BK current (I-BK) was blocked by the Ca2+ channel blockers Cd2+ (200 mu m) or nimodipine (1 mu m), and potentiated by FPL-64176 (1 mu m). I-BK was also 56% blocked by the BK channel blocker iberiotoxin (100 nm). I-BK activated more than 10-fold faster than the delayed rectifier I-Kv over the physiological voltage range, and partially inactivated. An AP-like command revealed that I-BK activated and deactivated faster than I-Kv and accounted for 86% of peak I-K, explaining why I-BK block increased AP height. A higher amplitude AP-like command, patterned on an AP recorded in 11.1 mm glucose plus paxilline, activated 4-fold more I-Kv and significantly increased Ca2+ entry. Paxilline increased insulin secretion in islets exposed to 11.1 mm glucose by 67%, but did not affect basal secretion in 2.8 mm glucose. These data suggest a modified model of beta-cell AP generation where I-BK and I-Kv coordinate the AP repolarisation.