Perspectives on Molecular Movements of Voltage Sensors

Olaf Sparre Andersen

Editor
The Journal of General Physiology

The purpose of the Perspectives in General Physiology is to provide a forum where scientific uncertainties or controversies can be discussed in an authoritative, yet open manner.

The Perspectives are solicited by the editors—often based on recommendations by the advisory editors or members of the editorial board, who may be asked to coordinate the process. To frame the issue, two or more experts will be invited to present a brief point of view on the problem, which will be published consecutively in The Journal. The comments and opinions expressed in the Perspectives are those of the authors and not necessarily those of the Editors or the Editorial Board. The Perspectives are accompanied by a few editorial paragraphs that introduce the problem—and invite the submission of comments, in the form of letters-to-the-editor, which will be published in a single, predetermined issue (usually four months after publication of the Perspective). After the letters-to-the-editor have been published, further responses will be limited to full manuscripts.

In this issue of the Journal, F. Bezanilla (University of California, Los Angeles), R. Horn (Jefferson Medical College), C.S. Gandhi and E. Isacoff (University of California, Berkeley), and H.P. Larsson (Oregon Health and Science University) provide different perspectives into the molecular movements underlying voltage-dependent cation channel gating and the coupling between the voltage sensor and the pore.

Some 30 yr ago, C.M. Armstrong and F. Bezanilla reported that the voltage-dependent increase in sodium channels' ion permeability is preceded by a gating charge. Though the charge movement was expected from Hodgkin and Huxley's pioneering kinetic analysis of the voltage-dependent conductance changes underlying sodium and potassium channel function, Armstrong and Bezanilla's observation was the first step toward a molecular understanding of channel gating. But what is the nature and extent of the molecular movement(s) underlying the gating current, and how is this charge movement coupled to channel activation? Despite the impressive advances in the kinetic analysis of voltage-gated channels, including Ca2+-activated potassium channels, which have appeared in the Journal over many years, the molecular motions underlying the gating charge movement remain controversial.

It is established that the fourth membrane-spanning segment (the S4 segment) in each subunit (or domain) is an important component of the voltage sensor, and a combination of chemical labeling and spectroscopic studies have shown that the gating charge movement is associated with a shift in the accessibility of charged residues in the S4 segment to the intracellular and extracellular solution, respectively. But what sort of molecular movement underlies this shift in accessibility (transfer "across" the membrane)? Is it a rotation, a translation, or a combination? And, once this question has been settled, how does the S4 movement (and associated changes in the surrounding channel protein) cause the conformational changes that lead to the conductance increase? One can reasonably be optimistic that the former question will be resolved in the not-too-distant future, given that it becomes a matter of resolving a physical movement, which may be elusive but nevertheless well-defined. The latter question is likely to remain unresolved for a longer time, as it becomes a matter of resolving the energetic coupling between the S4 segment motion and the state of the pore.

Letters-to-the-editor related to these Perspectives will be published in the February 2003 issue of the Journal of General Physiology. Letters-to-the-editor should be received no later than December 15, 2002, in order to allow for editorial review. The letters may be no longer than two printed pages (approximately six double-spaced pages) and will be subject to editorial review. They may contain no more than one figure, no more than 15 references, and no significant references to unpublished work. Letters should be prepared according to the Journal's instructions and can be submitted electronically at www.jgp.org, as an e-mail attachment to jgp{at}mail.rockefeller.edu, or sent as a hard copy (with accompanying diskette).





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