OHSU researchers identify structure linked to insulin secretion

KATP channel gating model
KATP channel gating model

It was more than 30 years ago that an ATP-sensitive potassium (KATP ) channel was identified as the key molecular link between glucose metabolism and insulin secretion.

The KATP channels sense metabolic changes and translate these energy fluxes into channel gating, which adjusts membrane excitability and regulates insulin secretion. They are the targets of the sulfonylureas, antidiabetic drugs that increase insulin release from beta cells in the pancreas. Genetic mutations of the channel cause several devastating rare diseases characterized by abnormal blood glucose control and neurological symptoms.

It is known that KATP channels are a complex of two proteins, Kir6.2 and SUR1, which are uniquely dependent on each other for expression and function. Still lacking, however, is detailed structural information crucial to understanding how the two proteins assemble and function as a complex in order to regulate insulin secretion.

Now, OHSU scientists have obtained the first subnanometer structure of the channel, which reveals the detailed domain organization of KATP channels and the intricate structural interactions between SUR1 and Kir6.2. The research team, consisting of the lead author Gregory Martin, a student in the Graduate Program in Molecular and Cellular Biosciences, senior authors Show-Ling Shyng, Ph.D., and James Chen, Ph.D., of the Department of Biochemistry and Molecular Biology, as well as Craig Yoshioka, Ph.D. of the Department of Biomedical Engineering and Matt Whorton, Ph.D. of the Vollum Institute published their findings on January 16 in eLife journal.

Single-particle cryo-electron microscopy (cryo-EM) conducted at the OHSU Multiscale Microscopy Core was used to construct a three-dimensional map of the KATP channel assembly and gating. 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 channel, hence release of insulin.

The new insight gained from the structure lays the foundation for future structural and functional studies. In particular, structures bound with various stimulatory and inhibitory ligands will further advance understanding of the detailed mechanisms of channel gating. This knowledge will aid in the design of more effective drugs to treat several devastating diseases caused by defective KATP channels.

An interesting observation in this research is that the ATP binding cassette (ABC) core of SUR1 is in a twisted inward-facing conformation, which suggests a possible mechanism by which the antidiabetic drug glibenclamide inhibits KATP channel activity. Because glibenclamide is known to inhibit the activity of other ABC transporter proteins—including cystic fibrosis transmembrane conductance regulator (CFTR) and the multidrug resistance protein MDR—the mechanism proposed by Shyng’s team could have implications much broader than insulin secretion disorders.

The research was supported by National Institutes of Health grants R01DK066485 (to SLS) and F31DK105800 (to GMM) as well as by the OHSU Core Pilot Grant Program, which is funded by the University Shared Resources program and the Office of the Senior Vice President for Research.

One response to “OHSU researchers identify structure linked to insulin secretion

  1. I am glad to see students I have worked with at OHSU going on to great work in other labs.

Comments are closed.