March 24, 2005
La Jolla, CA – Salk Institute for Biological Studies scientists have identified a tiny flexible gateway that controls the rapid-fire opening and closing of a family of ion channels through which potassium ions flow in and out of cells of the body.
Researchers study ion channels because they are crucial to the generation of the nerve impulses that enable the heart to beat, the body to move, and sensation and thought to occur.
Nerve impulses are generated when potassium and other ions exit and enter a cell through the pore-like channels that protrude through the cell membrane. The malfunction of these ion channels leads to several human diseases, including epilepsy, cardiac arrhythmias and muscle disorders.
Since the shape of a protein corresponds with its function, knowing the structure of the protein that makes up each family or type of potassium channel may enable Salk scientists and other researchers to define how these ion channels perform in health and disease.
The Salk Institute team, headed by Senyon Choe, Ph.D., and Paul Slesinger, Ph.D., showed that a family of ion channels named inwardly rectifying potassium (Kir) channels, has a unique closure device at one end. Like an elastic cuff, the closure device seems to control the movement of potassium in heart cells.
The findings are published in this month’s issue of Nature Neuroscience.
The Salk researchers first suspected a closure device in Kir channels because the passageway of these channels is too narrow to allow potassium or any other ions to enter or exit the cell.
“That was the first surprise,” said Slesinger, a co-senior author of the paper. “The fact that the opening was so narrow meant the channel would have to expand to permit the passage of ions through the channel.”
To pinpoint the parts of the ion channel structure that are important for it to function normally, Choe, Slesinger and colleagues compared two types of Kir channels found in rodent heart cells. The two types, named Kir2.1 and Kir3.1, are activated differently but both conduct potassium ions equally well in the open figuration.
Using painstaking detective work involving crystallography, molecular biology and electrophysiology, the Salk team revealed that the closure device is formed from structures called G-loops that surround the ‘mouth’ of the ion channel on the inside of the cell membrane. The researchers suspect that the G-loop complex operates like an elastic cuff that is closed in the resting position and expands to allow potassium ions out of the cell.
“The G-loops made good sense immediately when we saw them, and I was struck by their simplicity,” said Scott Pagan, a lead author of the paper.
Kir channels are important in medicine because they appear to have crucial roles in brain seizures including epilepsy, abnormal heart beats (heart arrhythmias), hyperactivity and developmental disorders. In 2001, University of Utah researchers showed that Andersen’s syndrome, a rare genetic disease involving cardiac arrhythmias, muscle paralysis and abnormal growth, is triggered by a mutation in the Kir2 channel.
“We can now visualize in the Kir2.1 structure where these mutations occur, providing new clues into the disease,” said Slesinger.
The next step, said Choe, is to demonstrate how this regulatory G-loop gateway actually closes the pore-like potassium channel. “Our goal now is to visualize how the regulatory part of the potassium channel is linked to the actual ion-flowing pore part across the cell membrane,” said Choe.
The National Institutes of Health and the McKnight Endowment for Neuroscience have helped to fund this research.
The Salk Institute for Biological Studies in La Jolla, California, is an independent nonprofit organization dedicated to fundamental discoveries in the life sciences, the improvement of human health and the training of future generations of researchers. Just five years after his polio vaccine in 1955 was proven safe and effective, Jonas Salk, M.D., founded the Institute with a gift of land from the City of San Diego and the financial support of the March of Dimes. Opening its doors in 1965, the Institute this year celebrates its 40th anniversary as well as the 50th anniversary of Dr. Salk’s polio vaccine.