Dec. 17, 1999 CHAMPAIGN, Ill. -- Scientists who performed the first direct measurement of voltage-induced distance changes in ion channels - critical components of the nervous system - have reached a surprising conclusion. As reported in the Dec.16 issue of Nature, the amino acids in the voltage sensor move like keys turning in locks, not like the simple plungers that were predicted by current models.
"Within nerve cell membranes, there are special pores - or channels - that regulate the flow of sodium and potassium ions," said Paul Selvin, a professor of physics at the University of Illinois. "The channels open and close like little gates, depending on the voltage across the membrane, and therefore control the generation and propagation of nerve impulses."
Because gene mutations in ion channels can cause neurological disorders, "a better understanding of how these channels work may aid in developing future treatments," said Francisco Bezanilla, the Hagiwara Professor of Neuroscience at the University of California at Los Angeles. "In this study, we wanted to find out how ion channels sense a change in voltage, and how the amino acids within the voltage sensors of the channels move when they open or close." To detect distances between specific sites in a potassium channel, graduate student Albert Cha at UCLA, graduate student Gregory Snyder at the U. of I., Bezanilla and Selvin combined a measurement technique called luminescence resonance energy transfer, developed in the Selvin laboratory, with a molecular biology labeling technique called site-directed mutagenesis. Cha performed the experiments at Bezanilla¹s lab at UCLA.
"We labeled particular amino acids within the ion channel, and then measured the change in distance as a function of voltage across the membrane," Bezanilla said. "The separation increased from 26.5 angstroms when the gate was closed, to 29.5 angstroms when the gate was fully open."
To determine the nature of that movement, Cha labeled other nearby sites and repeated their measurements. Surprisingly, some of these other amino acids moved apart, others moved closer together, and still others didn¹t appear to move at all.
"These motions are not consistent with a simple translational movement, like that of a plunger moving up and down within the membrane," Bezanilla said. "But a rotational motion - like the turning of a lock - fits the data nicely."
In both the open and closed states of the channel, there are charges that sit on the amino acids, Selvin said. The twisting of these amino acid segments exposes a different set of charges to the neighboring intracellular or extracellular fluid.
"We think the amino acids form crevice-like invaginations in the cell membrane," Selvin said. "The rotational motion changes the chemical accessibility of the charges from the inside of the cell to the outside of the cell. Thus, a small conformational change can cause a significant effect."
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