Catterall W, Epstein P N
Department of Pharmacology, School of Medicine, University of Washington, Seattle.
Diabetologia. 1992 Dec;35 Suppl 2:S23-33. doi: 10.1007/BF00586276.
Insulin secretion by the pancreatic Beta cell is dependent upon transmembrane ion fluxes gated by the ATP-regulated potassium channel and the voltage regulated, L-type calcium channel. This work group examined major recent advances in the structure and modulation of ion channels and how those advances may pertain to the physiology of insulin secretion and the pharmacological treatment of Type 2 (non-insulin-dependent) diabetes mellitus. Structural studies have revealed that voltage gated ion channels are related, complex, and comprised of multiple components: sodium channels consist of three distinct subunits. L-type calcium channels, crucial to the insulin secretory response are structurally related to the sodium channel but contain additional subunits. Potassium channels are less closely related and appear to function as homotetramers. Modulation of ion channel activity is similarly complex: site specific phosphorylation by multiple protein kinases under the control of several intracellular second messenger systems may increase or decrease conductance. Subunit composition and relatively stable changes in the modal state of ion channels also appear to be critical to ion channel gating properties. Functional studies of the Beta-cell ATP-regulated potassium channel suggest two distinct nucleotide binding sites which link this channel to the metabolic state of the Beta cell. The multiple paths of ion channel modulation provide multiple targets for therapeutic intervention. Where detailed characterisation of ion channel structure has been achieved, those targets are being used for specific drug design. Such complete characterisation has not yet been achieved for Beta-cell ion channels and this presents a major goal for diabetes research.
胰腺β细胞分泌胰岛素依赖于由ATP调节的钾通道和电压调节的L型钙通道控制的跨膜离子通量。该研究小组探讨了离子通道结构与调节方面的主要最新进展，以及这些进展如何与胰岛素分泌生理学和2型（非胰岛素依赖型）糖尿病的药物治疗相关。结构研究表明，电压门控离子通道相互关联、结构复杂且由多个组件组成：钠通道由三个不同的亚基组成。对胰岛素分泌反应至关重要的L型钙通道在结构上与钠通道相关，但含有额外的亚基。钾通道的相关性较低，似乎以同四聚体的形式发挥作用。离子通道活性的调节同样复杂：在几种细胞内第二信使系统的控制下，多种蛋白激酶进行的位点特异性磷酸化可能会增加或降低电导率。亚基组成以及离子通道模态状态相对稳定的变化似乎对离子通道的门控特性也至关重要。对β细胞ATP调节钾通道的功能研究表明存在两个不同的核苷酸结合位点，它们将该通道与β细胞的代谢状态联系起来。离子通道调节的多种途径为治疗干预提供了多个靶点。在已经实现离子通道结构详细表征的情况下，这些靶点正被用于特定药物设计。但β细胞离子通道尚未实现这样的完整表征，这是糖尿病研究的一个主要目标。
