Steve Mellon, Post-Gazette Dr. Michael Grabe, an assistant professor of biology at the University of Pittsburgh, has researched how charged particles flow in and out of cells and how cell doors in plants open and close. It's important research in understanding, among other things, how health problems occur when cell doors malfunction. Click photo for larger image.

The human cell is a tiny impoundment -- a busy little bubble city with many well-guarded gates that allow only specific things to enter and exit.

In healthy cells, potassium goes through one type of cell-membrane door, glucose through another and sodium through yet another.

How these cell doors -- known as channels and transporters -- operate has long been a biological mystery. But recent explanations are spawning hope of new treatments for epilepsy, heart arrhythmia and other ailments that result from interferences in cell-door processes.

In 2005, Roderick MacKinnon of the Howard Hughes Medical Institute and Rockefeller University shared the Nobel Prize in chemistry for describing what ion channels look like and how they operate.

Now a research team that includes Michael Grabe, an assistant professor of biology at the University of Pittsburgh College of Arts and Sciences, had a study published in Nature that describes an open ion channel in plant cells that helps to explain the appearance of closed channels in the human heart and brain.

Such queries are fundamental to understanding cell biology: "It always has been an important question of how to get things inside cells," Dr. Grabe said.

To display the complicated process, Dr. Grabe used the research to create a 3-D animation of the protein that serves as a channel for potassium ions, or potassium atoms with a positive electrical charge. It reveals how voltage sensors that surround the channel react to electrical impulses to open and close the channel.

In this case, Dr. Grabe said, the protein has four voltage sensors, each with four helices, surrounding the gateway.

As a visual reference, consider the channel to be Dolphin Stadium in Miami, with the field representing the part of the channel that opens and closes. The stadium has pairs of spiral ramps on each corner of the stadium, representing the voltage sensors, even though there are four spirals or helices in cell voltage centers. As these helix-shaped sensors spin in unison, they open the channel with a screwing or lever action.

When human cells build up a positive electrical charge inside, it activates voltage sensors to open and release the positively charged potassium ions and return the cell to a slightly negative charge, which is a comfortable resting state for the cell.

When the cell has a negative charge, the ion channel remains closed.

Normal cells have channels that allow potassium and sodium ions to flow between cells and create electrical impulses. Larger openings known as transporters let in glucose and proteins.

As it turns out, channels are specialized proteins that are critical to cell health. "If a door is always open, it won't work right," Dr. Grabe said. "You will lose all the heat in the house."

When the brain sends out a signal, neuron channels open to allow the charge to enter the cell, activating neighboring neurons to follow suit. Thus billions and billions of neurons transmit signals from the brain to muscles, organs or other body parts so they do their designated tasks.

Dr. Grabe's research explains how voltage sensors respond to electrical stimuli to open and close, much the way a small appliance would operate if plugged into an outlet.

Figuring out the biological puzzle was a major undertaking requiring creativity and keen understanding of the channel's genetic code.

They knew that the spiraling pair of voltage sensors -- those spiraling ramps at each corner of Dolphin Stadium -- must touch each other in precise ways to open and close the channel. Where they connect dictates how they twist, turn and perform their task, and what they look like when the door is opened and closed.

Researchers already knew the protein's genetic code, which spelled out the alignment of amino acids in plant cells.

So the team mutated a specific amino acid to kill the cell. Then they randomly made thousands of mutations of amino acids, one at a time, without changing the original mutated amino acid, until the cell channel finally began functioning again and the cell began growing.

Dr. Grabe said the process was like trying to randomly fix a complicated motor by twisting one screw at a time to repair it. But it worked.

The combination of mutations in two amino acids revealed which ones were working together, or connecting, to open and close the channel, thus returning the cell to good health.

That experiment revealed a blueprint of the voltage meters and how they operate.

"It showed which two amino acids were interacting," Dr. Grabe said. "We figured out which amino acids were talking to each other."

The research showed that opening and closing a channel involves large motions. A remaining question is whether the motion works like a screw or a lever to open and close the channel.

"It's something physical that occurs," Dr. Grabe said. "Exactly how, we still don't know."

Explaining these processes offers advances in a biological field that has become even hotter, Dr. Grabe said, ever since Dr. MacKinnon won the Nobel Prize.

Dr. Grabe, 33, is a native of Shippingport, Beaver County, and did his doctoral work at University of California, Berkeley. His role in the research involved doing all the computations. At the time, he was still at the University of California, San Francisco.

Ehud Isacoff, professor of neurobiology at Berkeley who is involved in similar research, described Dr. Grabe's as "the intellectual driving force behind the research.

"You have to simulate how the protein moves and that takes a lot of computer power and a lot of analytic prowess and tight logic," he said. "He combined them and came up with a model that is very satisfying and very intriguing.

"It's a first-time model that's pretty convincing."

It also largely agrees with the conclusions that Dr. Isacoff and his team came up with in their research published in the same edition of Nature. "The key thing is, we were very happy with the convergence of two analyses," he said.

Dr. Grabe said the research will open doors to new medications and biological understanding of cell operations.

"Now we're seeing how these big ion channels are put together and getting an idea how they rearrange themselves when they open and close," he said. "That will really help us understand the basic buildings blocks of how proteins have to move to do what they do."

Dr. Grabe said the research brings science one step closer to big answers.

"We're getting to a point with ion channels, where if something is wrong, we can tell you why it's happening," he said.