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October 12, 2016Nature CommunicationsOpen Access

The adamantane compound AC-1 potently inhibits Kv7.1/KCNE1 channels with an IC50 of 78.4 nM by binding to fenestrations that form only when KCNE1 accessory subunits are bound to Kv7.1 channels.

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Population

Kv7.1/KCNE1 channels (in vitro/preclinical model)

Design

Preclinical

Key result

The adamantane compound AC-1 potently inhibits Kv7.1/KCNE1 channels with an IC50 of 78.4 nM by binding to fenestrations that form only when KCNE1 accessory subunits are bound to Kv7.1 channels.

Authors

EWEva WrobelIRIna RothenbergCKChristoph Krisp

Discussion

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Overview

Offers selective probe for IKs research; leaves open therapeutic translation in channelopathies.

Structured PICO

P
Population
In vitro study using Xenopus oocytes and HEK293T cells to investigate the binding mechanism of adamantane derivatives to the Kv7.1/KCNE1 potassium channel complex.
I
Intervention
Adamantane derivatives (e.g., JNJ303)
O
Outcome
Binding site and putative access pathway for adamantane derivatives

Main Result

Effect estimate: IC50 78.4 nM

The discovery that KCNE1 induces fenestrations in Kv7.1 channels provides a structural basis for developing highly subtype-specific ion channel inhibitors.

Limitations

  • Due to limited resolution in MS/MS, it was not possible to explicitly identify a single AC-10-bound amino acid residue.
  • The existence of further lower affinity binding sites in the channel complex cannot be excluded.

Cite This Study

Wrobel et al. (2016) studied Kv7.1/KCNE1 channel function. AC-1 (JNJ303) vs. Control (homomeric Kv7.1 or no drug) was evaluated on Half-maximum inhibitory concentration (IC50) for Kv7.1/KCNE1 currents (IC50 78.4 nM). The adamantane compound AC-1 potently inhibits Kv7.1/KCNE1 channels with an IC50 of 78.4 nM by binding to fenestrations that form only when KCNE1 accessory subunits are bound to Kv7.1 channels.

synapsesocial.com/papers/6a557d4f0db8f4832a8e0d38https://doi.org/10.1038/ncomms12795
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