The Art of Timing
Channels in pancreatic cells control when insulin should be released to control blood sugar levels.
A hormone called insulin finely controls the amount of sugar in the blood. When the blood sugar content is high, a group of cells in the pancreas release insulin; when it is low, they stop. In these cells, the level of sugar in the blood modifies the ratio of two molecules: ATP, the body’s energy currency, and ADP, a molecule closely related to ATP. Changes in the ATP/ADP ratio are therefore a proxy of the variations in blood sugar levels.
In these pancreatic cells, a membrane protein called ATP sensitive potassium channel, KATP channel for short, acts as a switch that turns on and off the production of insulin. ATP and ADP control that switch, with the two molecules having opposite effects on the channel — ATP deactivates it, ADP activates it. The changes in ATP/ADP ratio — and by extension in blood sugar levels — are therefore coupled with the release of insulin.
However, how KATP channels sense the changes in the ATP/ADP ratio in these cells is still unclear. In particular, ATP levels are usually high and constant: ATP is then continuously deactivating the channels, and it is unclear how ADP ever activates them.
Here, Lee et al. use a microscopy technique that can image biological molecules at the atomic scale to look at the structure of human pancreatic KATP channels. The 3D reconstruction maps show that KATP channels have binding sites for ATP but also one for ADP. This ADP site acts as a sensor that can detect even small changes in ADP levels in the cell. The maps also reveal a dynamic lasso-like structure connecting the ATP and ADP binding areas. This domain may play a vital role in allowing ADP to override ATP’s control of the channel. The presence of the ADP sensor and the lasso structure could explain how KATP channels monitor changes in the ATP/ADP ratio and can therefore control the release of insulin based on blood sugar levels.
Defects in the KATP channels of the pancreas are present in genetic diseases where infants produce too much or too little insulin. Understanding the structure of these channels and how they work may help scientists to design new drugs to treat these conditions.
To find out more
Read the eLife research paper on which this eLife digest is based:
