Petit P, Loubatières-Mariani M M
Laboratoire de Pharmacologie, URA 599 du CNRS, Faculté de Médecine, Montpellier, France.
Fundam Clin Pharmacol. 1992;6(3):123-34. doi: 10.1111/j.1472-8206.1992.tb00103.x.
Ionic and electrical events play a central role in the stimulus-secretion coupling of the pancreatic B cell. Potassium permeability is critically involved in the regulation of B cell membrane potential and insulin secretion. In the absence of glucose, membrane potential remains stable, around -65 mV. This resting potential is mainly determined by the high potassium conductance of the membrane. The ATP generated by glucose metabolism in B cells blocks the K+(ATP) channels controlling resting membrane potential. Thus, glucose metabolism leads to closure of the ATP-dependent potassium channels; the resulting decrease in K+ permeability induces depolarization and opening of voltage-activated Ca-channels. The subsequent increase in Ca2+ influx raises the cytoplasmic concentration of free Ca2+, which in turn triggers exocytosis of secretory granules. Other types of K+ channels have also been identified in the B cell, such as voltage- and Ca(2+)-dependent K+ channels, which are not a target for the action of glucose, but may play a role in the repolarization of spikes. The modulation of insulin release by some hormones and neurotransmitters involves, among other mechanisms, an interference with the plasma membrane K+ conductance. Thus, galanine, somatostatin and adrenaline, which inhibit insulin release, increase K+ conductance by a G protein-dependent mechanism; both peptides were reported to open ATP-sensitive K+ channels in insulin-secreting cell line RINm5F. It was also observed that extracellular purine nucleotides could interfere with K+ channels. Among the various drugs interfering with insulin secretion, sulfonylureas, such as tolbutamide and glibenclamide, directly inhibit ATP-dependent K+ channels in the B cell membrane and thereby initiate insulin release. In contrast, potassium channel openers such as diazoxide, antagonize the effects of glucose by increasing K+ permeability of the B cell membrane. Furthermore, other classes of drugs have recently been shown to interact with K+ (ATP) channels. Thus, K+ channels of the pancreatic B cell, particularly ATP-dependent ones, play a crucial role in the electrophysiology of insulin secretion; they are an important target for pharmacological agents designed to modulate this secretion.
离子和电活动在胰腺β细胞的刺激-分泌偶联中起核心作用。钾离子通透性在β细胞膜电位和胰岛素分泌的调节中起关键作用。在无葡萄糖的情况下，膜电位保持稳定，约为 -65 mV。这种静息电位主要由膜的高钾离子电导率决定。β细胞中葡萄糖代谢产生的ATP会阻断控制静息膜电位的K+(ATP)通道。因此，葡萄糖代谢导致ATP依赖性钾通道关闭；钾离子通透性的降低会引起去极化并导致电压激活的钙通道开放。随后钙离子内流增加，使细胞质中游离钙离子浓度升高，进而触发分泌颗粒的胞吐作用。在β细胞中还发现了其他类型的钾通道，如电压依赖性和钙(2+)依赖性钾通道，它们不是葡萄糖作用的靶点，但可能在动作电位的复极化中起作用。一些激素和神经递质对胰岛素释放的调节，除其他机制外，还涉及对质膜钾离子电导率的干扰。因此，抑制胰岛素释放的甘丙肽、生长抑素和肾上腺素，通过G蛋白依赖性机制增加钾离子电导率；据报道，这两种肽都能使胰岛素分泌细胞系RINm5F中的ATP敏感性钾通道开放。还观察到细胞外嘌呤核苷酸会干扰钾通道。在各种干扰胰岛素分泌的药物中，磺脲类药物，如甲苯磺丁脲和格列本脲，直接抑制β细胞膜中的ATP依赖性钾通道，从而引发胰岛素释放。相反，钾通道开放剂，如二氮嗪，通过增加β细胞膜的钾离子通透性来拮抗葡萄糖的作用。此外，最近还发现其他类药物可与K+(ATP)通道相互作用。因此，胰腺β细胞的钾通道，尤其是ATP依赖性钾通道，在胰岛素分泌的电生理学中起关键作用；它们是设计用于调节这种分泌的药物的重要靶点。
