Molecular mechanism of voltage-dependent potentiation of KCNH potassium channels
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.
Article and author information
Author details
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.
Reviewing Editor
- Baron Chanda, University of Wisconsin-Madison, United States
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.
Version history
- Received: February 25, 2017
- Accepted: April 24, 2017
- Accepted Manuscript published: April 26, 2017 (version 1)
- Accepted Manuscript updated: April 27, 2017 (version 2)
- Version of Record published: May 22, 2017 (version 3)
Copyright
© 2017, Dai & Zagotta
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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