Tetraphenylporphyrin derivative specifically blocks members of the voltage-gated potassium channel subfamily Kv1

Sönke Hornig, Iris Ohmert, Dirk Trauner, Christian Ader, Marc Baldus, Olaf Pongs

Research output: Contribution to journalArticle

Abstract

Tetraphenylporphyrin derivatives represent a promising class of high-affinity ligands for voltage-gated potassium (Kv) channels. Herein, we investigated the mode of Kv channel block of one tetraphenylporphyrin derivative, por3, using electrophysiological methods, structure-based mutagenesis, and solid-state NMR spectroscopy. The combined data showed that por3 specifically blocks Kv1.x channels. Unexpectedly, 2 different por3 binding modes lead to Kv1.x channel block exerted through multiple por3 binding sites: first, por3 interacts in a highly cooperative and specific manner with the voltage sensor domain stabilizing closed Kv1 channel state(s). Therefore, stronger depolarization is needed to activate Kv1.x channels in the presence of por3. Second, por3 bind to a single site at the external pore entrance to block the ion conduction pathway of activated Kv1.x channels. This block is voltage-independent. Por3 appears to have equal affinities for voltage-sensor and pore. However, at negative voltage and low por3 concentration, por3 gating modifier properties prevail due to the high cooperativity of binding. By contrast, at positive voltages, when Kv1.x channels are fully activated, por3 pore blocking properties predominate.

Original languageEnglish (US)
Article numbera11
JournalChannels
Volume7
Issue number6
DOIs
StatePublished - 2013

Fingerprint

Voltage-Gated Potassium Channels
Derivatives
Electric potential
Mutagenesis
Magnetic Resonance Spectroscopy
Binding Sites
Ions
Ligands
Sensors
Depolarization
Nuclear magnetic resonance spectroscopy
tetraphenylporphyrin

Keywords

  • Gating modifier
  • Liposomes
  • Porphyrin
  • Solid-state NMR
  • Voltage-gated potassium-channel

ASJC Scopus subject areas

  • Biophysics
  • Medicine(all)
  • Biochemistry

Cite this

Tetraphenylporphyrin derivative specifically blocks members of the voltage-gated potassium channel subfamily Kv1. / Hornig, Sönke; Ohmert, Iris; Trauner, Dirk; Ader, Christian; Baldus, Marc; Pongs, Olaf.

In: Channels, Vol. 7, No. 6, a11, 2013.

Research output: Contribution to journalArticle

Hornig, Sönke ; Ohmert, Iris ; Trauner, Dirk ; Ader, Christian ; Baldus, Marc ; Pongs, Olaf. / Tetraphenylporphyrin derivative specifically blocks members of the voltage-gated potassium channel subfamily Kv1. In: Channels. 2013 ; Vol. 7, No. 6.
@article{0c4b512153234288b7d62560193550e0,
title = "Tetraphenylporphyrin derivative specifically blocks members of the voltage-gated potassium channel subfamily Kv1",
abstract = "Tetraphenylporphyrin derivatives represent a promising class of high-affinity ligands for voltage-gated potassium (Kv) channels. Herein, we investigated the mode of Kv channel block of one tetraphenylporphyrin derivative, por3, using electrophysiological methods, structure-based mutagenesis, and solid-state NMR spectroscopy. The combined data showed that por3 specifically blocks Kv1.x channels. Unexpectedly, 2 different por3 binding modes lead to Kv1.x channel block exerted through multiple por3 binding sites: first, por3 interacts in a highly cooperative and specific manner with the voltage sensor domain stabilizing closed Kv1 channel state(s). Therefore, stronger depolarization is needed to activate Kv1.x channels in the presence of por3. Second, por3 bind to a single site at the external pore entrance to block the ion conduction pathway of activated Kv1.x channels. This block is voltage-independent. Por3 appears to have equal affinities for voltage-sensor and pore. However, at negative voltage and low por3 concentration, por3 gating modifier properties prevail due to the high cooperativity of binding. By contrast, at positive voltages, when Kv1.x channels are fully activated, por3 pore blocking properties predominate.",
keywords = "Gating modifier, Liposomes, Porphyrin, Solid-state NMR, Voltage-gated potassium-channel",
author = "S{\"o}nke Hornig and Iris Ohmert and Dirk Trauner and Christian Ader and Marc Baldus and Olaf Pongs",
year = "2013",
doi = "10.4161/chan.25848",
language = "English (US)",
volume = "7",
journal = "Channels",
issn = "1933-6950",
publisher = "Landes Bioscience",
number = "6",

}

TY - JOUR

T1 - Tetraphenylporphyrin derivative specifically blocks members of the voltage-gated potassium channel subfamily Kv1

AU - Hornig, Sönke

AU - Ohmert, Iris

AU - Trauner, Dirk

AU - Ader, Christian

AU - Baldus, Marc

AU - Pongs, Olaf

PY - 2013

Y1 - 2013

N2 - Tetraphenylporphyrin derivatives represent a promising class of high-affinity ligands for voltage-gated potassium (Kv) channels. Herein, we investigated the mode of Kv channel block of one tetraphenylporphyrin derivative, por3, using electrophysiological methods, structure-based mutagenesis, and solid-state NMR spectroscopy. The combined data showed that por3 specifically blocks Kv1.x channels. Unexpectedly, 2 different por3 binding modes lead to Kv1.x channel block exerted through multiple por3 binding sites: first, por3 interacts in a highly cooperative and specific manner with the voltage sensor domain stabilizing closed Kv1 channel state(s). Therefore, stronger depolarization is needed to activate Kv1.x channels in the presence of por3. Second, por3 bind to a single site at the external pore entrance to block the ion conduction pathway of activated Kv1.x channels. This block is voltage-independent. Por3 appears to have equal affinities for voltage-sensor and pore. However, at negative voltage and low por3 concentration, por3 gating modifier properties prevail due to the high cooperativity of binding. By contrast, at positive voltages, when Kv1.x channels are fully activated, por3 pore blocking properties predominate.

AB - Tetraphenylporphyrin derivatives represent a promising class of high-affinity ligands for voltage-gated potassium (Kv) channels. Herein, we investigated the mode of Kv channel block of one tetraphenylporphyrin derivative, por3, using electrophysiological methods, structure-based mutagenesis, and solid-state NMR spectroscopy. The combined data showed that por3 specifically blocks Kv1.x channels. Unexpectedly, 2 different por3 binding modes lead to Kv1.x channel block exerted through multiple por3 binding sites: first, por3 interacts in a highly cooperative and specific manner with the voltage sensor domain stabilizing closed Kv1 channel state(s). Therefore, stronger depolarization is needed to activate Kv1.x channels in the presence of por3. Second, por3 bind to a single site at the external pore entrance to block the ion conduction pathway of activated Kv1.x channels. This block is voltage-independent. Por3 appears to have equal affinities for voltage-sensor and pore. However, at negative voltage and low por3 concentration, por3 gating modifier properties prevail due to the high cooperativity of binding. By contrast, at positive voltages, when Kv1.x channels are fully activated, por3 pore blocking properties predominate.

KW - Gating modifier

KW - Liposomes

KW - Porphyrin

KW - Solid-state NMR

KW - Voltage-gated potassium-channel

UR - http://www.scopus.com/inward/record.url?scp=84892174514&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84892174514&partnerID=8YFLogxK

U2 - 10.4161/chan.25848

DO - 10.4161/chan.25848

M3 - Article

VL - 7

JO - Channels

JF - Channels

SN - 1933-6950

IS - 6

M1 - a11

ER -