BIOPHYSICS
Molecular mechanism of pH sensing in KcsA potassium channels
Department of Anesthesiology, and Department of Physiology and Biophysics, Weill Cornell Medical College, New York City, NY 10065
Edited by Christopher Miller, Brandeis University, Waltham, MA, and approved February 20, 2008 (received for review January 28, 2008)
Abstract
The bacterial potassium channel KcsA is gated by high concentrations of intracellular protons, allowing the channel to open at pH < 5.5. Despite prior attempts to determine the mechanism responsible for pH gating, the proton sensor has remained elusive. We have constructed a KcsA channel mutant that remains open up to pH 9.0 by replacing key ionizable residues from the N and C termini of KcsA with residues mimicking their protonated counterparts with respect to charge. A series of individual and combined mutations were investigated by using single-channel recordings in lipid bilayers. We propose that these residues are the proton-binding sites and at neutral pH they form a complex network of inter- and intrasubunit salt bridges and hydrogen bonds near the bundle crossing that greatly stabilize the closed state. In our model, these residues change their ionization state at acidic pH, thereby disrupting this network, modifying the electrostatic landscape near the channel gate, and favoring channel opening.
ion channel | proton sensor | salt bridge network | pH gating
Author contributions: A.N.T. and D.J.P. contributed equally to this work; A.N.T., D.J.P., and C.M.N. designed research; A.N.T., D.J.P., and P.V.P. performed research; A.N.T., D.J.P., and C.M.N. analyzed data; and A.N.T., D.J.P., and C.M.N. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
*To whom correspondence should be addressed. E-mail: crn2002{at}med.cornell.edu
© 2008 by The National Academy of Sciences of the USA
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg What's this?
