Suppr超能文献

三磷酸腺苷敏感性钾通道的药理学伴侣:低温电镜结构的机制见解。

Pharmacological chaperones of ATP-sensitive potassium channels: Mechanistic insight from cryoEM structures.

机构信息

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.

出版信息

Mol Cell Endocrinol. 2020 Feb 15;502:110667. doi: 10.1016/j.mce.2019.110667. Epub 2019 Dec 9.

Abstract

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.

摘要

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。

相似文献

1
Pharmacological chaperones of ATP-sensitive potassium channels: Mechanistic insight from cryoEM structures.
Mol Cell Endocrinol. 2020 Feb 15;502:110667. doi: 10.1016/j.mce.2019.110667. Epub 2019 Dec 9.
2
Pharmacological Correction of Trafficking Defects in ATP-sensitive Potassium Channels Caused by Sulfonylurea Receptor 1 Mutations.
J Biol Chem. 2016 Oct 14;291(42):21971-21983. doi: 10.1074/jbc.M116.749366. Epub 2016 Aug 29.
4
Pharmacological rescue of trafficking-impaired ATP-sensitive potassium channels.
Front Physiol. 2013 Dec 24;4:386. doi: 10.3389/fphys.2013.00386.
5
Production and purification of ATP-sensitive potassium channel particles for cryo-electron microscopy.
Methods Enzymol. 2021;653:121-150. doi: 10.1016/bs.mie.2021.02.008. Epub 2021 Mar 22.
6
Mechanism of pharmacochaperoning in a mammalian K channel revealed by cryo-EM.
Elife. 2019 Jul 25;8:e46417. doi: 10.7554/eLife.46417.
8
ATP binding without hydrolysis switches sulfonylurea receptor 1 (SUR1) to outward-facing conformations that activate K channels.
J Biol Chem. 2019 Mar 8;294(10):3707-3719. doi: 10.1074/jbc.RA118.005236. Epub 2018 Dec 26.
9
Mechanistic insights on KATP channel regulation from cryo-EM structures.
J Gen Physiol. 2023 Jan 2;155(1). doi: 10.1085/jgp.202113046. Epub 2022 Nov 28.
10
Pancreatic β-cell KATP channels: Hypoglycaemia and hyperglycaemia.
Rev Endocr Metab Disord. 2010 Sep;11(3):157-63. doi: 10.1007/s11154-010-9144-2.

引用本文的文献

2
AI-based discovery and cryoEM structural elucidation of a K channel pharmacochaperone.
Elife. 2025 Mar 26;13:RP103159. doi: 10.7554/eLife.103159.
3
AI-Based Discovery and CryoEM Structural Elucidation of a K Channel Pharmacochaperone.
bioRxiv. 2025 Feb 7:2024.09.05.611490. doi: 10.1101/2024.09.05.611490.
4
Non-radioactive Rb Efflux Assay for Screening K Channel Modulators.
Methods Mol Biol. 2024;2796:191-210. doi: 10.1007/978-1-0716-3818-7_12.
5
Exploring the Pathophysiology of ATP-Dependent Potassium Channels in Insulin Resistance.
Int J Mol Sci. 2024 Apr 6;25(7):4079. doi: 10.3390/ijms25074079.
9
From glucose sensing to exocytosis: takes from maturity onset diabetes of the young.
Front Endocrinol (Lausanne). 2023 May 15;14:1188301. doi: 10.3389/fendo.2023.1188301. eCollection 2023.
10
K channel mutations in congenital hyperinsulinism: Progress and challenges towards mechanism-based therapies.
Front Endocrinol (Lausanne). 2023 Mar 28;14:1161117. doi: 10.3389/fendo.2023.1161117. eCollection 2023.

本文引用的文献

2
Ion Channels of the Islets in Type 2 Diabetes.
J Mol Biol. 2020 Mar 6;432(5):1326-1346. doi: 10.1016/j.jmb.2019.08.014. Epub 2019 Aug 30.
4
Mechanism of pharmacochaperoning in a mammalian K channel revealed by cryo-EM.
Elife. 2019 Jul 25;8:e46417. doi: 10.7554/eLife.46417.
5
Structural identification of a hotspot on CFTR for potentiation.
Science. 2019 Jun 21;364(6446):1184-1188. doi: 10.1126/science.aaw7611.
6
The Structural Basis for the Binding of Repaglinide to the Pancreatic K Channel.
Cell Rep. 2019 May 7;27(6):1848-1857.e4. doi: 10.1016/j.celrep.2019.04.050.
7
Molecular structure of the ATP-bound, phosphorylated human CFTR.
Proc Natl Acad Sci U S A. 2018 Dec 11;115(50):12757-12762. doi: 10.1073/pnas.1815287115. Epub 2018 Nov 20.
8
Cryo-EM Visualization of an Active High Open Probability CFTR Anion Channel.
Biochemistry. 2018 Oct 30;57(43):6234-6246. doi: 10.1021/acs.biochem.8b00763. Epub 2018 Oct 16.
9
Therapies and outcomes of congenital hyperinsulinism-induced hypoglycaemia.
Diabet Med. 2019 Jan;36(1):9-21. doi: 10.1111/dme.13823. Epub 2018 Oct 8.
10
Genetic characteristics of patients with congenital hyperinsulinism.
Curr Opin Pediatr. 2018 Aug;30(4):568-575. doi: 10.1097/MOP.0000000000000645.

文献AI研究员

20分钟写一篇综述,助力文献阅读效率提升50倍。

立即体验

用中文搜PubMed

大模型驱动的PubMed中文搜索引擎

马上搜索

文档翻译

学术文献翻译模型,支持多种主流文档格式。

立即体验