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Published online on September 18, 2006, 10.1073/pnas.0606660103 OPEN ACCESS ARTICLE


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Biophysics
Electrostatic interactions in the channel cavity as an important determinant of potassium channel selectivity

( inward rectification | permeation | permeability | GIRK modeling | Kir3 )

Delphine Bichet, Michael Grabe *, Yuh Nung Jan, and Lily Yeh Jan {dagger}

Departments of Physiology and Biochemistry and Howard Hughes Medical Institute, University of California, San Francisco, CA 94143

Contributed by Lily Yeh Jan, August 2, 2006

Potassium channels are membrane proteins that allow the passage of potassium ions at near diffusion rates while severely limiting the flux of the slightly smaller sodium ions. Although studies thus far have focused on the narrowest part of the channel, known as the selectivity filter, channels are long pores with multiple ions that traverse the selectivity filter, the water-filled central cavity, and the rest of the pore formed by cytoplasmic domains. Here, we present experimental analyses on Kir3.2 (GIRK2), a G protein-activated inwardly rectifying potassium (Kir) channel, showing that a negative charge introduced at a pore-facing position in the cavity (N184) below the selectivity filter restores both K+ selectivity and inward rectification properties to the nonselective S177W mutant channel. Molecular modeling demonstrates that the negative residue has no effect on the geometry of the selectivity filter, suggesting that it has a local effect on the cavity ion. Moreover, restoration of selectivity does not depend on the exact location of the charge in the central cavity as long as this residue faces the pore, where it is in close contact with permeant ions. Our results indicate that interactions between permeant ions and the channel cavity can influence ion selectivity and channel block by means of an electrostatic effect.

Author contributions: D.B. and M.G. designed research; D.B. and M.G. performed research; D.B. and M.G. analyzed data; and D.B., M.G., Y.N.J., and L.Y.J. wrote the paper.

The authors declare no conflict of interest.

Freely available online through the PNAS open access option.

*Present address: Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260.

{dagger}To whom correspondence should be addressed.

Lily Yeh Jan, E-mail: lily.jan{at}ucsf.edu

www.pnas.org/cgi/doi/10.1073/pnas.0606660103
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