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Mimicry of a Host Anion Channel by a Helicobacter pylori Pore-Forming Toxin

Daniel M. Czajkowsky ^*, Hideki Iwamoto , Gabor Szabo ^*, Timothy L. Cover  and Zhifeng Shao ^*

^* Department of Molecular Physiology and Biological Physics, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908; and Department of Pharmacology and Departments of Medicine and Microbiology and Immunology, Vanderbilt University School of Medicine and Veterans Affairs Medical Center, Nashville, Tennessee 37232

Correspondence: Address reprint requests to Timothy L. Cover, A2200 Medical Center North, Vanderbilt University School of Medicine, Nashville, TN 37232. Tel.: 615-322-2035; Fax: 615-343-6160; E-mail: timothy.l.cover{at}vanderbilt.edu; or Zhifeng Shao, Room 480, Jordan Hall, University of Virginia School of Medicine, Charlottesville, VA 22908. Tel.: 434-982-0829; Fax: 434-243-2981; E-mail: zs9q{at}virginia.edu.

Bacterial pore-forming toxins have traditionally been thought to function either by causing an essentially unrestricted flux of ions and molecules across a membrane or by effecting the transmembrane transport of an enzymatically active bacterial peptide. However, the Helicobacter pylori pore-forming toxin, VacA, does not appear to function by either of these mechanisms, even though at least some of its effects in cells are dependent on its pore-forming ability. Here we show that the VacA channel exhibits two of the most characteristic electrophysiological properties of a specific family of cellular channels, the ClC channels: an open probability dependent on the molar ratio of permeable ions and single channel events resolvable as two independent, voltage-dependent transitions. The sharing of such peculiar properties by VacA and host ClC channels, together with their similar magnitudes of conductance, ion selectivities, and localization within eukaryotic cells, suggests a novel mechanism of toxin action in which the VacA pore largely mimics the electrophysiological behavior of a host channel, differing only in the membrane potential at which it closes. As a result, VacA can perturb, but not necessarily abolish, the homeostatic ionic imbalance across a membrane and so change cellular physiology without necessarily jeopardizing vitality.

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