In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 96, No. 26 ( 1999-12-21), p. 15298-15303
Kurzfassung:
Inward-rectifier K + channels of the ROMK (K ir 1.1) subtype are responsible for K + secretion and control of NaCl absorption in the kidney. A hallmark of these channels is their gating by intracellular pH in the neutral range. Here we show that a lysine residue close to TM1, identified previously as a structural element required for pH-induced gating, is protonated at neutral pH and that this protonation drives pH gating in ROMK and other K ir channels. Such anomalous titration of this lysine residue (Lys-80 in K ir 1.1) is accomplished by the tertiary structure of the K ir protein: two arginines in the distant N and C termini of the same subunit (Arg-41 and Arg-311 in K ir 1.1) are located in close spatial proximity to the lysine allowing for electrostatic interactions that shift its pK a into the neutral pH range. Structural disturbance of this triad as a result from a number of point mutations found in patients with antenatal Bartter syndrome shifts the pK a of the lysine residue off the neutral pH range and results in channels permanently inactivated under physiological conditions. Thus, the results provide molecular understanding for normal pH gating of K ir channels as well as for the channel defects found in patients with antenatal Bartter syndrome.
Materialart:
Online-Ressource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.96.26.15298
Sprache:
Englisch
Verlag:
Proceedings of the National Academy of Sciences
Publikationsdatum:
1999
ZDB Id:
209104-5
ZDB Id:
1461794-8
SSG:
11
SSG:
12
