Study reveals how a tiny protein senses all the communications in a cell

Washington, August 1 : New research by Johns Hopkins scientists shed light on how the calcium sensor protein calmodulin can gauge both the local flow of calcium, in through the closest channel, and the global calcium flow entering the many channels across the entire cell.

"It's like being at a cocktail party where the easiest person to listen to is the one closest to you, but we all have the ability to keep an ear out for other interesting conversations going on throughout the room. It turns out that calmodulin is doing a similar thing, sensing the calcium coming through the closest channel through one ear while the other ear 'listens' to the calcium coming through distant channels across the cell," says Dr. David Yue, a professor of biomedical engineering at Hopkins.

Calmodulin is normally positioned right near each calcium channel, according to the background information in a research article published in the journal Cell.

It had already been discovered years ago that calmodulin can somehow switch its sensory focus between local calcium and global calcium entering the cell through channels at a distance.

Dr. Yue says that the calmodulin protein is made of two ball-like lobes, which act as the different calcium-sensing "ears".

The researcher says that the C lobe listens locally and the N lobe listens globally, across the whole cell.

With a view to determining how calmodulin's two lobes can sense different sources of calcium, the researchers took a two-pronged approach.

First, they used computers to perform mathematical simulations that tested different potential calcium detection mechanisms of the calmodulin lobes.

Previous studies have shown that the C lobe of calmodulin hangs onto calcium for a long time, whereas the N lobe lets go rapidly.

The computer simulations used in the current study suggested that the slight differences in calcium holding time might play a role in calmodulin's ability to sense both local and global calcium levels.

"Once a local calcium ion sticks to the C lobe, it seldom lets go, and so the local calcium dominates," says Dr. Yue.

By contrast, the N lobe would rapidly let go of calcium, and then be empty and available to bind calcium entering the cell from distant calcium channels, allowing reception of global calcium.

The research team then verified their mathematical predictions by testing real calmodulin proteins attached to calcium channels.

With the help of a new approach, the group could precisely controll calcium pulses through single calcium channels, and watch how calmodulin responded.

Dr. Yue says that understanding the language of calcium is critical for understanding how cells communicate, and also important for understanding neural diseases.

The researcher feels that early antipsychotic drugs may work by blocking calmodulin action.

"Now that we are learning how these drugs actually work, we can contribute our new understanding of calmodulin to the design of next-generation drugs with greater potency and fewer side effects," Dr. Yue says.

ANI