Gating of the TREK-2 ion channel

Post by Pande Lab member Keri McKiernan (kmckiern)

The class of proteins that mediate the conduction of ions across the membrane of electrically excitable cells are referred to as ion channels. In analogy to electronics, ion channels are similar to transistors, which mediate the flow of electrons in a circuit. The rate at which ions are able to flow through an ion channel is determined by the conformational state of the protein. External stimuli, such as drug binding or sudden changes in membrane tension, are able to induce conformational changes in these proteins. These events ‘gate’ the channel, such that protein conductance changes in accordance with its local environment.

The TREK-2 potassium ion channel has two ‘gates’. One is given by the arrangement of the intracellular helicies (M2, M3, and M4). The other is given by the conformation of the channel selectivity filter (SF). We applied computer simulations in order to study the relationship between TREK-2 gating and membrane stretch. In other words, when the membrane pushes or pulls on this protein, how does that affect ion conduction?

We found that the intracellular gate assumes 2 major states (Up and Down). Below is a movie generated from our dataset, showing the protein transitioning between these states.

Additionally, we identified two conformational states of the SF (Open and Pinched). Note that existence of the Pinched SF state is novel and has not been confirmed by experiment. Our analysis suggests that the intracellular and SF gates could be strongly coupled. We hypothesize that when TREK-2 is compressed by the surrounding membrane, the intracellular gate transitions to the Down state, and the SF transitions to the Pinched state, resulting in drastically diminished ion conduction. When TREK-2 is stretched, it assumed a high conductivity state, with the intracellular gate in the Up state, and the SF in the Open state.

For technical details, we refer you to our publication: 10.1038/s41598–017–00256-y