Cryo-EM structure of the ATP-sensitive potassium channel illuminates mechanisms of assembly and gating

eLife journal

Gregory M Martin¹ 

DOI  :  10.7554/eLife.24149.001

学科分类：医学（综合）

来源: eLife Sciences Publications, Ltd

【 摘 要 】

The hormone insulin reduces blood sugar levels by encouraging fat, muscle and other body cells to take up sugar. When blood sugar levels rise following a meal, cells within the pancreas known as beta cells should release insulin. In people with diabetes, the beta cells fail to release insulin, meaning that the high blood sugar levels are not corrected. When blood sugar levels are high, beta cells generate more energy in the form of ATP molecules. The increased level of ATP causes channels called ATP-sensitive potassium (KATP) channels in the membrane of the cell to close. This triggers a cascade of events that leads to the release of insulin. Some treatments for diabetes alter how the KATP channels work. For example, a widely prescribed medication called glibenclamide (also known as glyburide in the United States) stimulates the release of insulin by preventing the flow of potassium through KATP channels. It remains unknown exactly how ATP and glibenclamide interact with the channel’s molecular structure to stop the flow of potassium ions. KATP channels are made up of two proteins called SUR1 and Kir6.2. To investigate the structure of the KATP channel, Martin et al. purified channels made of the hamster form of the SUR1 protein and the mouse form of Kir6.2, which each closely resemble their human counterparts. The channels were purified in the presence of ATP and glibenclamide and were then rapidly frozen to preserve their structure, which allowed them to be visualized individually using electron microscopy. By analyzing the images taken from many channels, Martin et al. constructed a highly detailed, three-dimensional map of the KATP channel. The structure revealed by this map shows how SUR1 and Kir6.2 work together and provides insight into how ATP and glibenclamide interact with the channel to block the flow of potassium, and hence stimulate the release of insulin. An important next step will be to improve the structure to more clearly identify where ATP and glibenclamide bind to the KATP channel. It will also be important to study the structures of channels that are bound to other regulatory molecules. This will help researchers to fully understand how KATP channels located throughout the body operate under healthy and diseased conditions. This knowledge will aid in the design of more effective drugs to treat several devastating diseases caused by defective KATP channels.

【 授权许可】

CC BY