Neutralization of a single arginine residue gates open a two-pore domain, alkali-activated K+ channel

Niemeyer, MI; Gonzalez-Nilo, FD; Zuniga, L; Gonzalez, W; Cid, LP; Sepulveda, FV

Abstract

Potassium channels share a common selectivity filter that determines the conduction characteristics of the pore. Diversity in K+ channels is given by how they are gated open. TASK-2, TALK-1, and TALK-2 are two-pore region (2P) KCNK K+ channels gated open by extracellular alkalinization. We have explored the mechanism for this alkalinization-dependent gating using molecular simulation and site-directed mutagenesis followed by functional assay. We show that the side chain of a single arginine residue (R224) near the pore senses pH in TASK-2 with an unusual pKa of 8.0, a shift likely due to its hydrophobic environment. R224 would block the channel through an electrostatic effect on the pore, a situation relieved by its deprotonation by alkalinization. A lysine residue in TALK-2 fulfills the same role but with a largely unchanged pKa, which correlates with an environment that stabilizes its positive charge. In addition to suggesting unified alkaline pH-gating mechanisms within the TALK subfamily of channels, our results illustrate in a physiological context the principle that hydrophobic environment can drastically modulate the pKa of charged amino acids within a protein. © 2006 by The National Academy of Sciences of the USA.

Más información

Título según WOS: Neutralization of a single arginine residue gates open a two-pore domain, alkali-activated K+ channel
Título según SCOPUS: Neutralization of a single arginine residue gates open a two-pore domain, alkali-activated K+ channel
Título de la Revista: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volumen: 104
Número: 2
Editorial: NATL ACAD SCIENCES
Fecha de publicación: 2007
Página de inicio: 666
Página final: 671
Idioma: English
URL: http://www.pnas.org/cgi/doi/10.1073/pnas.0606173104
DOI:

10.1073/pnas.0606173104

Notas: ISI, SCOPUS