pH gating of ROMK (Kir1.1) channels:: Control by an Arg-Lys-Arg triad disrupted in antenatal Bartter syndrome
pH gating of ROMK (Kir1.1) channels:: Control by an Arg-Lys-Arg triad disrupted in antenatal Bartter syndrome
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DOI：
10.1073/pnas.96.26.15298
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发表时间：
1999-12-21
影响因子：
11.1
通讯作者：
Ludwig, J
中科院分区：
文献类型：
--
作者：
Schulte, U;Hahn, H;Ludwig, J
ROMK(K(Ir)1.1)亚型的内向整流性K+通道负责肾脏K+的分泌和对氯化钠吸收的控制。这些通道的一个特点是它们通过细胞内pH在中性范围内进行门控。在这里，我们证明了接近TM1的赖氨酸残基，以前被认为是pH诱导门控所需的结构元件，在中性pH下质子化，这种质子化驱动ROMK和其他K-Ir通道的pH门控。这种异常的赖氨酸残基(K(Ir)1.1中的Lys-80)的滴定是由K-ir蛋白的三级结构完成的：同一亚基(K(Ir)1.1中的Arg-41和Arg-311)的N和C末端的两个精氨酸位于靠近赖氨酸的空间位置，允许静电相互作用使其pK(A)移动到中性pH范围。这种三联体的结构紊乱是由于在产前巴特综合征患者中发现的一些点突变导致的，使赖氨酸残基的pK(A)偏离中性pH范围，并导致通道在生理条件下永久失活。因此，这些结果为了解正常pH门控的K-ir通道以及产前巴特综合征患者中发现的通道缺陷提供了分子基础。
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.