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Inverse coupling in leak and voltage-activated K+ channel gates underlies distinct roles in electrical signaling

Abstract

Voltage-activated (Kv) and leak (K2P) K+ channels have key, yet distinct, roles in electrical signaling in the nervous system. Here we examine how differences in the operation of the activation and slow inactivation pore gates of Kv and K2P channels underlie their unique roles in electrical signaling. We report that (i) leak K+ channels possess a lower activation gate, (ii) the activation gate is an important determinant controlling the conformational stability of the K+ channel pore, (iii) the lower activation and upper slow inactivation gates of leak channels cross-talk and (iv) unlike Kv channels, where the two gates are negatively coupled, these two gates are positively coupled in K2P channels. Our results demonstrate how basic thermodynamic properties of the K+ channel pore, particularly conformational stability and coupling between gates, underlie the specialized roles of Kv and K2P channel families in electrical signaling.

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Figure 1: Leak channels contain a lower activation gate.
Figure 2: Mutations of hydrophobic residues in the activation gate to glycine stabilize the open state of the Shaker channel.
Figure 3: Mutations of glycine residues in the activation gate to hydrophobic residues result in a reduction in the open probability of the KCNK0 leak channel.
Figure 4: Hydrophobic activation gate mutants of the KCNK0 leak channel induce closure of the upper inactivation gate.
Figure 5: Hydrophobic activation gate mutants of the KCNK0 leak channel induce closure of the lower activation gate.
Figure 6: A simplified schematic thermodynamic cycle connecting the four possible K+ channel pore states, where the lower activation (A) and upper slow inactivation (I) pore gates are either closed (C) or open (O).

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Acknowledgements

We thank C. Deutsch for valuable comments and insight on this manuscript. O.Y. is the incumbent of the Belle and Murray Nathan Career Development Chair in Neurobiology. N.Z. is the incumbent of the Murray and Judith Shusterman Career Development Chair in Microbiology. This research was funded by grants from the Bi-national (US-Israel) Science Foundation (BSF) to O.Y., Y.Z and N.Z. (grant 2005112) and the Israel Science Foundation (ISF) grant to N.Z. (grant 431/03).

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O.Y. and N.Z. designed the research; Y.B. performed the research; O.Y., N.Z. and Y.B. analyzed the data, Y.Z contributed new insights/analytical tools and O.Y. wrote the paper.

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Correspondence to Noam Zilberberg or Ofer Yifrach.

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Ben-Abu, Y., Zhou, Y., Zilberberg, N. et al. Inverse coupling in leak and voltage-activated K+ channel gates underlies distinct roles in electrical signaling. Nat Struct Mol Biol 16, 71–79 (2009). https://doi.org/10.1038/nsmb.1525

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