Studies on multimolecular modulation of ATP-sensitive K^+ channels in pancreatic β-cells

atp敏感的K^+通道由磺脲受体单元和内整流K^+通道孔单元的异聚体组成。细胞内Ca^<2+>可抑制磺脲类药物与受体结合和通道关闭之间的功能转导。氧自由基对细胞内代谢的抑制导致磺脲类药物对通道抑制作用的降低。细胞内ATP也是这些亚基之间信号转导的调节剂之一，但需要降低到<10 μM的浓度才能抑制磺脲诱导的通道关闭。肌动蛋白（细胞骨架蛋白）维持了磺脲类药物对通道的抑制作用，而PIP_2（质膜磷脂）通过拮抗细胞内Ca^<2+>来稳定肌动蛋白的作用，据报道，Ca^<2+>可使肌动蛋白丝从f -肌动蛋白解聚为g -肌动蛋白。PBP_2还通过降低ATP的敏感性来增加通道的活性。此外，我们发现细胞外施加的ATP刺激p2y受体，通过降低膜PIP_2水平，导致心脏ATP敏感的K^+通道活性降低。这些结果表明，膜PIP_2水平可能是通道基础活性的决定因素。我们提出通道是由周围分子调节的：膜磷脂，Ca^<2+>，肌动蛋白丝和ATP。

ATP-sensitive K^+ channels are composed of heteromultimers of sulfonylurea-receptor unit and pore unit of inwardly rectifying K^+ channels. Intracellular Ca^<2+> was found to inhibit functional transduction between binding of sulfonylureas to their receptors and closure of channels. Inhibition of intracellular metabolism by oxygen-free radicals resulted in a reduction of inhibitory efficacy of channels by sulfonylureas. Intracellular ATP was also one of modulators of signal transduction between these subunits, but was required to be decreased to concentrations <10 μM for inhibition of sulfonylurea-induced closure of the channel. Actin, cytoskeletal proteins, maintained the inhibitory effect of sulfonylureas on the channel, and PIP_2, plasma membrane phospholipids, stabilizes the actin effect by antagonizing intracellular Ca^<2+> that is reported to depolymerize actin filaments from F-actin to G-actin. PBP_2 also increased activity of the channel by reducing ATP sensitivity. Furthermore, we found that stimulation of P2Y-receptors by extracellularly applied ATP resulted in reduction of activity of cardiac ATP-sensitive K^+ channels via reduction of membrane PIP_2 levels. These results suggest that levels of membrane PIP_2 may be a determinant of basal activity of the channels. We propose that the channel is modulated by surrounding molecules: membrane phospholipids, Ca^<2+>, actin filaments and ATP.