Molecular mechanism of voltage-dependent potentiation of KCNH potassium channels

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Abstract

EAG-like (ELK) voltage-gated potassium channels are abundantly expressed in the brain. These channels exhibit a behavior called voltage-dependent potentiation (VDP), which appears to be a specialization to dampen the hyperexitability of neurons. VDP manifests as a potentiation of current amplitude, hyperpolarizing shift in voltage sensitivity, and slowing of deactivation in response to a depolarizing prepulse. Here we show that VDP of D. rerio ELK channels involves the structural interaction between the intracellular N-terminal eag domain and C-terminal CNBHD. Combining transition metal ion FRET, patch-clamp fluorometry, and incorporation of a fluorescent noncanonical amino acid, we show that there is a rearrangement in the eag domain-CNBHD interaction with the kinetics, voltage-dependence, and ATP-dependence of VDP. We propose that the activation of ELK channels involves a slow open-state dependent rearrangement of the direct interaction between the eag domain and CNBHD, which stabilized the opening of the channel.

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Gucan Dai

Department of Physiology and Biophysics, University of Washington, Seattle, United States

Competing interests
The authors declare that no competing interests exist.
William N Zagotta

Department of Physiology and Biophysics, University of Washington, Seattle, United States

For correspondence
zagotta@uw.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-7631-8168

Funding

National Institute of Mental Health (R01MH102378)

William N Zagotta

National Eye Institute (R01EY010329)

William N Zagotta

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to an approved institutional animal care and use committee (IACUC) protocol (#2689-01 ) of the University of Washington.

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