Rocheleau Jonathan V, Remedi Maria S, Granada Butch, Head W Steven, Koster Joseph C, Nichols Colin G, Piston David W
Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
PLoS Biol. 2006 Feb;4(2):e26. doi: 10.1371/journal.pbio.0040026. Epub 2006 Jan 17.
Pancreatic beta-cells secrete insulin in response to closure of ATP-sensitive K+ (KATP) channels, which causes membrane depolarization and a concomitant rise in intracellular Ca2+ (Cai). In intact islets, beta-cells are coupled by gap junctions, which are proposed to synchronize electrical activity and Cai oscillations after exposure to stimulatory glucose (>7 mM). To determine the significance of this coupling in regulating insulin secretion, we examined islets and beta-cells from transgenic mice that express zero functional KATP channels in approximately 70% of their beta-cells, but normal KATP channel density in the remainder. We found that KATP channel activity from approximately 30% of the beta-cells is sufficient to maintain strong glucose dependence of metabolism, Cai, membrane potential, and insulin secretion from intact islets, but that glucose dependence is lost in isolated transgenic cells. Further, inhibition of gap junctions caused loss of glucose sensitivity specifically in transgenic islets. These data demonstrate a critical role of gap junctional coupling of KATP channel activity in control of membrane potential across the islet. Control via coupling lessens the effects of cell-cell variation and provides resistance to defects in excitability that would otherwise lead to a profound diabetic state, such as occurs in persistent neonatal diabetes mellitus.
胰腺β细胞在ATP敏感性钾通道（KATP）关闭时分泌胰岛素，这会导致细胞膜去极化并伴随细胞内钙离子（Cai）浓度升高。在完整胰岛中，β细胞通过缝隙连接相互耦联，有人提出在暴露于刺激性葡萄糖（>7 mM）后，缝隙连接可使电活动和Cai振荡同步。为了确定这种耦联在调节胰岛素分泌中的重要性，我们研究了来自转基因小鼠的胰岛和β细胞，这些小鼠约70%的β细胞中功能性KATP通道表达为零，其余细胞中的KATP通道密度正常。我们发现，约30%的β细胞的KATP通道活性足以维持完整胰岛代谢、Cai、膜电位和胰岛素分泌对葡萄糖的强烈依赖性，但在分离的转基因细胞中葡萄糖依赖性丧失。此外，抑制缝隙连接会导致转基因胰岛中特异性丧失葡萄糖敏感性。这些数据表明，KATP通道活性的缝隙连接耦联在控制整个胰岛的膜电位方面起着关键作用。通过耦联进行控制可减轻细胞间差异的影响，并对兴奋性缺陷提供抗性，否则这些缺陷会导致严重的糖尿病状态，如持续性新生儿糖尿病中所发生的那样。
