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Jefferson scientists uncover new clues to how crucial molecular gatekeepers work
October 12, 2005Understanding how voltage-gated ion channels operate is requisite for improving disease treatment
One of the biggest mysteries in molecular biology is exactly how ion channels - tiny protein pores through which molecules such as calcium and potassium flow in and out of cells - operate. Such channels can be extremely important; members of the voltage-gated ion channel family are crucial to generating electrical pulses in the brain and heart, carrying signals in nerves and muscles. When channel function goes awry, the resulting diseases - known as channelopathies, including epilepsy, a number of cardiomyopathies and cystic fibrosis - can be devastating.
Ion channels are also controversial, with two competing theories of how they open and close. Now, scientists at Jefferson Medical College, reporting October 6, 2005 in the journal Neuron, have detailed a part of this intricate process, providing evidence to support one of the theories. A better understanding of how these channels work is key to developing new drugs to treat ion channel-based disorders.
According to Richard Horn, Ph.D., professor of physiology at Jefferson Medical College of Thomas Jefferson University in Philadelphia, voltage-gated ion channels are large proteins with a pore that pierces the cell membrane. They open and close in response to voltage changes across the cell membrane, and the channels determine when and which ions are permitted to cross a cell membrane.
In the conventional theory, when an electrical impulse called an action potential travels along a nerve, the cell membrane charge changes. The inside of the cell (normally electrically negative), becomes more positive. In turn, the voltage sensor, a positively charged transmembrane segment called S4, moves towards the outside of the cell through a small molecular gasket called a gating pore. This movement somehow causes the ion channel to open, releasing positively charged ions to flow across the cell membrane. After the action potential is over, the cell's inside becomes negative again, and the membrane returns to its normal resting state.
The more recent and controversial theory proposed by Nobel laureate Roderick MacKinnon of Rockefeller University holds that a kind of molecular paddle comprised of the S4 segment and part of the S3 segment moves through the cell membrane, carrying S4's positive charges with it across the lipid. As in the conventional theory, the S4 movement controls the channel's opening and closing. The two theories differ in part because the paddle must move its positive charges all the way across the cell membrane. The conventional theory says that charges move a short distance through the gating pore.
In the current work, Dr. Horn and colleague Christopher Ahern, Ph.D., a research assistant in the Department of Physiology at Jefferson Medical College, showed that the field through which the voltage sensor's charges moved is very short, lending support to the conventional model.
"Using a molecular tape measure with a very fine resolution - 1.24 Angstroms - we tethered charges to the voltage sensor," Dr. Horn explains. "When the tether is too long, the voltage sensor can't pull it through the electric field," meaning the electric field is highly focused.
"This is another nail in the coffin of the paddle model," he says, \\\
Thomas Jefferson University
According to Richard Horn, Ph.D., professor of physiology at Jefferson Medical College of Thomas Jefferson University in Philadelphia, voltage-gated ion channels are large proteins with a pore that pierces the cell membrane. They open and close in response to voltage changes across the cell membrane, and the channels determine when and which ions are permitted to cross a cell membrane.
In the conventional theory, when an electrical impulse called an action potential travels along a nerve, the cell membrane charge changes. The inside of the cell (normally electrically negative), becomes more positive. In turn, the voltage sensor, a positively charged transmembrane segment called S4, moves towards the outside of the cell through a small molecular gasket called a gating pore. This movement somehow causes the ion channel to open, releasing positively charged ions to flow across the cell membrane. After the action potential is over, the cell's inside becomes negative again, and the membrane returns to its normal resting state.
The more recent and controversial theory proposed by Nobel laureate Roderick MacKinnon of Rockefeller University holds that a kind of molecular paddle comprised of the S4 segment and part of the S3 segment moves through the cell membrane, carrying S4's positive charges with it across the lipid. As in the conventional theory, the S4 movement controls the channel's opening and closing. The two theories differ in part because the paddle must move its positive charges all the way across the cell membrane. The conventional theory says that charges move a short distance through the gating pore.
In the current work, Dr. Horn and colleague Christopher Ahern, Ph.D., a research assistant in the Department of Physiology at Jefferson Medical College, showed that the field through which the voltage sensor's charges moved is very short, lending support to the conventional model.
"Using a molecular tape measure with a very fine resolution - 1.24 Angstroms - we tethered charges to the voltage sensor," Dr. Horn explains. "When the tether is too long, the voltage sensor can't pull it through the electric field," meaning the electric field is highly focused.
"This is another nail in the coffin of the paddle model," he says, \\\
Thomas Jefferson University
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Since the discovery in 2007 that a component of human semen called SEVI boosts infectivity of the virus that causes AIDS, researchers have been trying to learn more about SEVI and how it works, in hopes of thwarting its infection-promoting activity.
Texas A&M Researchers Examine How Viruses Destroy Bacteria
Viruses are well known for attacking humans and animals, but some viruses instead attack bacteria. Texas A&M University researchers are exploring how hungry viruses, armed with transformer-like weapons, attack bacteria, which may aid in the treatment of bacterial infections.
Research reveals lipids' unexpected role in triggering death of brain cells
The lipid that accumulates in brain cells of individuals with an inherited enzyme disorder also drives the cell death that is a hallmark of the disease, according to new research led by St. Jude Children's Research Hospital investigators.
New explanation for nature's hardiest life form
Got food poisoning? The cause might be bacterial spores, en extremely hardy survival form of bacteria, a nightmare for health care and the food industry and an enigma for scientists.
Hoping for a fluorescent basket case
Although recent advances have raised hopes that a protective vaccine can be developed, acquired immunodeficiency syndrome (AIDS) remains a major public health problem.
Cholesterol-lowering medicines may be effective against cancer
Statins lower cholesterol by blocking certain enzymes involved in our metabolism.
New approach for growing bone comes from Duke preclinical research
The natural cycle of building bone to maintain skeletal strength and then breaking it down for the body's calcium needs is delicately balanced, but diseases like osteoporosis break down too much bone without adequate bone replacement, leading to bone fractures.
NEDD9 Protein Supports Growth of Aggressive Breast Cancer
Researchers at Fox Chase Cancer Center have demonstrated that a protein called NEDD9 may be required for some of the most aggressive forms of breast cancer to grow. Their findings, based on the study of a mouse model of breast cancer, are presented in a recent issue of Cancer Research, available on-line now.
Study shows how disruption of spectrin-actin network causes lens cells in the eye to lose shape
A network of proteins underlying the plasma membrane keeps epithelial cells in shape and maintains their orderly hexagonal packing in the mouse lens, say Nowak et al.
Cell discovery opens new chapter in drug development
British scientists have uncovered new details about how the cells in our bodies communicate with each other and their environment: findings that are of fundamental importance to human biology.
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