J Cell Physiol 2014 Nov 01;22911:1703-21. doi: 10.1002/jcp.24616.

Gating of the kir2.1 channel at the bundle crossing region by intracellular spermine and other cations.

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In the Kir2.1 channel, the flow-dependent blocking effect of intracellular spermine (SPM) strongly indicates coupled movement of ions in a segment of the pore. We have shown that the bundle crossing region of M2 constitutes this critical segment of the pore. Moreover, this segment may undergo opening/closing conformational changes mimicking channel gating. In this study, we further investigate these "gating" conformational changes and relevant controlling mechanisms at this critical segment. We demonstrate that A184R mutation in the inner end of the bundle crossing region not only abolishes the inward rectifying features of SPM block but also tends to close the channel pore, which can then only be opened by intracellular (e.g., Na(+) , or equally effectively, K(+) ) but not extracellular cations. We also found that the exit (back to the intracellular milieu) of the blocking in the deep site is facilitated rather than deterred by the presence of the other SPM in the superficial site. We conclude that intracellular SPM may bind to a deep site in the pore and serve as a flow-dependent blocker. The SPM in the superficial site, on the other hand, serves both as a docking form ready for permeation to the deep site, and as a gating particle capable of opening the bundle crossing region. This inner end of the bundle crossing region of the Kir2.1 channel pore thus constitutes a pivotal segment, which, in collaboration with intracellular SPM and K(+) ions, closely couple channel gating to (inward rectifying) ion permeation.

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Species referenced: Xenopus
Genes referenced: kcnj2