Key result
Mutations affecting GH loop flexibility (e.g., V223L, E272G, D292G) increased both on- and off-gating kinetics of Kir2 channels.
The cytosolic GH loop plays a novel role in regulating the PIP2-induced gating kinetics of Kir2 channels through competing interactions with the CD loop.
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No immediate clinical implications for channelopathies; extends mechanistic understanding of Kir2 gating but leaves translation open.
Inwardly rectifying K(+) (Kir) channels set the resting membrane potential and regulate cellular excitability. The activity of Kir channels depends critically on the phospholipid PIP(2). The molecular mechanism by which PIP(2) regulates Kir channel gating is poorly understood. Here, we utilized a combination of computational and electrophysiological approaches to discern structural elements involved in regulating the PIP(2)-induced gating kinetics of Kir2 channels. We identify a novel role for the cytosolic GH loop. Mutations that directly or indirectly affect GH loop flexibility (e.g. V223L, E272G, D292G) increase both the on- and especially the off-gating kinetics. These effects are consistent with a model in which competing interactions between the CD and GH loops for the N terminus regulate the gating of the intracellular G loop gate.
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An et al. (2012) studied Kir2 channel gating. Mutations affecting GH loop flexibility (e.g., V223L, E272G, D292G) was evaluated on PIP(2)-induced gating kinetics. Mutations affecting GH loop flexibility (e.g., V223L, E272G, D292G) increased both on- and off-gating kinetics of Kir2 channels.
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