Department of Chemical Physiology and Biochemistry, Oregon Health & Science University, Portland, OR, 97239, USA.
Department of Chemical Physiology and Biochemistry, Oregon Health & Science University, Portland, OR, 97239, USA.
Mol Cell Endocrinol. 2020 Feb 15;502:110667. doi: 10.1016/j.mce.2019.110667. Epub 2019 Dec 9.
ATP-sensitive potassium (K) channels are uniquely evolved protein complexes that couple cell energy levels to cell excitability. They govern a wide range of physiological processes including hormone secretion, neuronal transmission, vascular dilation, and cardiac and neuronal preconditioning against ischemic injuries. In pancreatic β-cells, K channels composed of Kir6.2 and SUR1, encoded by KCNJ11 and ABCC8, respectively, play a key role in coupling blood glucose concentration to insulin secretion. Mutations in ABCC8 or KCNJ11 that diminish channel function result in congenital hyperinsulinism. Many of these mutations principally hamper channel biogenesis and hence trafficking to the cell surface. Several small molecules have been shown to correct channel biogenesis and trafficking defects. Here, we review studies aimed at understanding how mutations impair channel biogenesis and trafficking and how pharmacological ligands overcome channel trafficking defects, particularly highlighting recent cryo-EM structural studies which have shed light on the mechanisms of channel assembly and pharmacological chaperones.
ATP 敏感性钾 (K) 通道是一种独特进化的蛋白质复合物,它将细胞能量水平与细胞兴奋性联系起来。它们调控着广泛的生理过程,包括激素分泌、神经元传递、血管扩张以及心脏和神经元对缺血性损伤的预处理。在胰腺 β 细胞中,由 KCNJ11 和 ABCC8 分别编码的 Kir6.2 和 SUR1 组成的 K 通道在将血糖浓度与胰岛素分泌偶联中发挥关键作用。ABCC8 或 KCNJ11 突变会降低通道功能,导致先天性高胰岛素血症。这些突变主要妨碍了通道的生物发生和运输到细胞表面。已经有几种小分子被证明可以纠正通道生物发生和运输缺陷。在这里,我们综述了旨在了解突变如何损害通道生物发生和运输以及药理学配体如何克服通道运输缺陷的研究,特别强调了最近的冷冻电镜结构研究,这些研究揭示了通道组装和药理学伴侣的机制。