Publication

Understanding the flow of potassium ions across cell membranes

Authors: Daniel Minor (University of California, San Francisco; Lawrence Berkeley National Laboratory)
Co-authored by industrial partner: No

Type: Diamond Annual Review Highlight

State: Published (Approved)
Published: July 2021

Abstract: The flow of potassium ions across the cell membrane is regulated by K2P potassium channels, controlling electrical activity in the brain, heart and nervous system. These channels have important roles in pain, migraine, depression, anaesthetic responses, arrhythmias, hypertension and lung injury responses. K channels regulate ion flow using a selectivity filter (C-type) gate. However, previous 2P structural studies have not captured the gating mechanisms, and they remain poorly understood. Currently, there are no drugs available that selectively target K2P potassium channels. To develop new ways to control their function, we need to understand more about the gating mechanisms and their roles in human biology. In work published in Science Advances, researchers from Diamond Light Source, University of California, San Francisco and the University Pittsburgh, USA, combined X-ray crystallography in different potassium concentrations, potassium anomalous scattering, molecular dynamics and electrophysiology to uncover the changes that occur in K2P C-type gating. At Diamond, the team used the Long-Wavelength Macromolecular Crystallography (MX) beamline (I23) to observe changes in potassium ions within the channel directly. I23 is the only beamline in the world optimised to measure signals from potassium ions directly, and its unique capabilities were central to these studies. The results show that K2P gating involves pinching and dilation of two key elements of the channel selectivity filter gate. These structural changes are accompanied by the loss of potassium ions. Including a small molecule activator (ML335) suppressed these changes and demonstrated how stabilisation of the selectivity filter gate facilitates ion flow through the channel. These studies show that small molecule activators bind to and stabilise the K2P selectivity filter gate, preventing the pinching and dilation conformational changes and loss of potassium ions that lead to channel inactivation. These findings open a path to develop new K2P channel- directed drugs to treat pain, ischemia (restricted blood flow), depression and lung injury.

Journal Keywords: K potassium channel; K 2.1 (TREK-1); C-type gate; Selectivity filter

Subject Areas: Biology and Bio-materials, Chemistry


Instruments: I23-Long wavelength MX

Added On: 12/11/2021 15:53

Discipline Tags:

Life Sciences & Biotech Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX) Long Wavelength Crystallography