Visualizing CNS proteins: A Native-State Structural Biology Platform

The brain’s remarkable ability to generate thoughts, regulate emotions, and orchestrate bodily functions arises from a delicate balance of electrical signals. When this balance is disrupted, brain function is impaired, sometimes with serious and irreversible consequences.

At the heart of this signaling are specialized membrane proteins called ion channels. These channels sit in the membranes that surround every brain cell, generating electrical signals by controlling the flow of charged particles (ions) into and out of the cell. Each type of channel is regulated in a unique way, and this precise control makes complex brain signaling possible. 

To truly understand how the brain works, we need to understand how these channels behave. Imagine designing a computer: engineers must understand how each circuit element functions. If a component malfunctions, the entire system can fail. The same is true for the brain–without understanding how its fundamental components work, we can’t understand how it works or how best to fix it when something goes wrong. 

A critical step to understanding how ion channels work is knowing what they look like. Existing methods to visualize ion channels require removing them from their cellular membrane environment, which distorts their shape. Since the membrane environment of the channel profoundly influences its shape, there is an urgent need for approaches that preserve it. This project meets this need by developing a new platform to visualize ion channels inside brain-cell membranes, using cryo-electron microscopy, an advanced visualization technology, to take ultra-detailed pictures of these proteins. 

To demonstrate the power of this approach, I will study CLC-2, a brain-specific ion channel linked to neurological disorders. More broadly, this platform offers a new way to study membrane proteins inside cells, helping unlock long-elusive mechanisms of brain function and guide future treatments.