1. Departments of Physiology and Anesthesiology, David Geffen School of Medicine, UCLA, 650 Charles E. Young Dr. South, Los Angeles, California 90025, USA
2. Department of Physiology and Biophysics, Weill Medical College, Cornell University, 1300 York Avenue, New York, New York 10021, USA
3. Centro de Estudios Cientificos, Valdivia, Chile
4. †Present address: Department of Emergency Medicine, University of New Mexico Health Sciences Campus, Albuquerque, New Mexico 87106, USA

Correspondence to: Francisco Bezanilla^1,3 Correspondence and requests for materials should be addressed to F.B. (Email: fbezanil@ucla.edu)

Abstract

Voltage-gated ion channels are responsible for generating electrical impulses in nerves and other excitable cells. The fourth transmembrane helix (S4) in voltage-gated channels is the primary voltage-sensing unit that mediates the response to a changing membrane electric field^{1, 2}. The molecular mechanism of voltage sensing, particularly with respect to the magnitude of the transmembrane movement of S4, remains controversial^{3, 4, 5}. To determine the extent of this transmembrane movement, we use fluorescent resonance energy transfer between the S4 domain and a reference point in the lipid bilayer. The lipophilic ion dipicrylamine distributes on either side of the lipid bilayer depending on the membrane potential, and is used here as a resonance-energy-transfer acceptor from donor molecules attached to several positions in the Shaker K⁺ channel. A voltage-driven transmembrane movement of the donor should produce a transient fluorescence change because the acceptor also translocates as a function of voltage. In Shaker K⁺ channels no such transient fluorescence is observed, indicating that the S4 segment does not translocate across the lipid bilayer. Based on these observations, we propose a molecular model of voltage gating that can account for the observed 13e gating charge with limited transmembrane S4 movement.

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