pH gating of ROMK (Kir1.1) channels: Control by an Arg-Lys-Arg triad disrupted in antenatal Bartter syndrome

Inward-rectifier K+ channels of the ROMK (Kir1.1) 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 Kir channels. Such anomalous titration of this lysine residue (Lys-80 in Kir1.1) is accomplished by the tertiary structure of the Kir protein: two arginines in the distant N and C termini of the same subunit (Arg-41 and Arg-311 in Kir1.1) are located in close spatial proximity to the lysine allowing for electrostatic interactions that shift its pKa 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 pKa 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 Kir channels as well as for the channel defects found in patients with antenatal Bartter syndrome.

Antenatal screening and its possible meaning from unborn baby's perspective

In recent decades antenatal screening has become one of the most routine procedure of pregnancy-follow up and the subject of hot debate in bioethics circles. In this paper the rationale behind doing antenatal screening and the actual and potential problems that it may cause will be discussed. The paper will examine the issue from the point of wiew of parents, health care professionals and, most importantly, the child-to-be. It will show how unthoughtfully antenatal screening is performed and how pregnancy is treated almost as a disease just since the emergence of antenatal screening. Genetic screening and ethical problems caused by the procedure will also be addressed and I will suggest that screening is more to do with the interests of others rather than those of the child-to be.