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Niemeyer, M.I. et al.

Niemeyer, Gonz??lez-Nilo, Z????iga, Gonz??lez, Cid, Sep??lveda,

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

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 pK(a) 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 pK(a), 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 pK(a) of charged amino acids within a protein.[1]

References

Neutralization of a single arginine residue gates open a two-pore domain, alkali-activated K+ channel. Niemeyer, M.I., Gonz??lez-Nilo, F.D., Z????iga, L., Gonz??lez, W., Cid, L.P., Sep??lveda, F.V. Proc. Natl. Acad. Sci. U.S.A. (2007) [Pubmed]

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