One of the biggest mysteries in molecular biology is exactly how ionchannels -- tiny protein pores through which molecules such as calciumand potassium flow in and out of cells -- operate. Such channels can beextremely important; members of the voltage-gated ion channel familyare crucial to generating electrical pulses in the brain and heart,carrying signals in nerves and muscles. When channel function goesawry, the resulting diseases -- known as channelopathies, includingepilepsy, a number of cardiomyopathies and cystic fibrosis -- can bedevastating.
Ion channels are also controversial, with two competing theories ofhow they open and close. Now, scientists at Jefferson Medical College,reporting October 6, 2005 in the journal Neuron, have detailed a partof this intricate process, providing evidence to support one of thetheories. A better understanding of how these channels work is key todeveloping new drugs to treat ion channel-based disorders.
According to Richard Horn, Ph.D., professor of physiology atJefferson Medical College of Thomas Jefferson University inPhiladelphia, voltage-gated ion channels are large proteins with a porethat pierces the cell membrane. They open and close in response tovoltage changes across the cell membrane, and the channels determinewhen and which ions are permitted to cross a cell membrane.
In the conventional theory, when an electrical impulse called an actionpotential travels along a nerve, the cell membrane charge changes. Theinside of the cell (normally electrically negative), becomes morepositive. In turn, the voltage sensor, a positively chargedtransmembrane segment called S4, moves towards the outside of the cellthrough a small molecular gasket called a gating pore. This movementsomehow causes the ion channel to open, releasing positively chargedions to flow across the cell membrane. After the action potential isover, the cell's inside becomes negative again, and the membranereturns to its normal resting state.
The more recent and controversial theory proposed by Nobellaureate Roderick MacKinnon of Rockefeller University holds that a kindof molecular paddle comprised of the S4 segment and part of the S3segment moves through the cell membrane, carrying S4's positive chargeswith it across the lipid. As in the conventional theory, the S4movement controls the channel's opening and closing. The two theoriesdiffer in part because the paddle must move its positive charges allthe way across the cell membrane. The conventional theory says thatcharges 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 atJefferson Medical College, showed that the field through which thevoltage sensor's charges moved is very short, lending support to theconventional model.
"Using a molecular tape measure with a very fine resolution --1.24 Angstroms -- we tethered charges to the voltage sensor," Dr. Hornexplains. "When the tether is too long, the voltage sensor can't pullit through the electric field," meaning the electric field is highlyfocused.
"This is another nail in the coffin of the paddle model," hesays, "because the thickness of the electric field is much smaller thanpredicted by that model. The measurement is unambiguous in terms of therelationship between length of the tether and how much charge getspulled through the electric field.
Next, the researchers are tackling the relationship between S4's movement and the gates that open and close the channels.
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