DGIST researchers identify molecular 'lever' controlling brain cell calcium channels

A research team led by Seo Byung-chang, a professor in the Department of Brain Sciences at DGIST (Daegu Gyeongbuk Institute of Science and Technology), announced Wednesday that it has become the first in the world to identify a new molecular mechanism regulating the N-type voltage-gated calcium channel, which plays a critical role in signal transmission between neurons.

Neurons convert electrical signals into chemical signals to pass information to the next cell. The entry of calcium ions into a cell through voltage-gated calcium channels is the most essential step in that process. The team identified the existence and operating principle of what it calls a "molecular lever" that opens and closes the calcium channel, offering a key clue for developing next-generation treatments for brain diseases.

How long a calcium channel stays open varies depending on which type of auxiliary protein — known as a beta (β) subunit — binds to it. How exactly these subunits alter the channel's structure had remained unknown.

By comparing and analyzing models with various beta subunits, the team noticed that a specific region of the channel where the auxiliary protein binds was distinctively bent. Their research revealed that this region acts as a pivot point, with the surrounding loop functioning like a "lever" that shifts the channel's structure to different angles depending on which beta subunit is attached. The team said it was the first in the world to propose a structural-change model for calcium channels based on the movement of this molecular lever.

The team measured the channel's open and closed states using electrophysiology techniques and applied kinetic modeling to confirm that these structural changes are a critically important part of neuronal signal transmission. The findings are expected to serve as a milestone in developing treatments for a range of intractable brain conditions involving calcium channels, including neuropathic pain, epilepsy, autism spectrum disorder and Alzheimer's disease.

"Through this research, we have clearly identified the kinetic and structural changes in calcium channels caused by beta subunit binding — a question that had long remained unanswered," Seo said. "We expect this to contribute to the development of treatments for various brain diseases, including epilepsy, autism spectrum disorder and Alzheimer's."

The study, supported by the National Research Foundation of Korea, was published in the Proceedings of the National Academy of Sciences (PNAS).