Tetraphenylporphyrin derivative specifically blocks members of the voltage-gated potassium channel subfamily Kv1
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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, Jahrgang 7, Nr. 6, 2013, S. 473-82.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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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 - Animals
KW - Ion Channel Gating
KW - Porosity
KW - Porphyrins
KW - Potassium Channel Blockers
KW - Shaker Superfamily of Potassium Channels
KW - Substrate Specificity
KW - Xenopus laevis
U2 - 10.4161/chan.25848
DO - 10.4161/chan.25848
M3 - SCORING: Journal article
C2 - 24722265
VL - 7
SP - 473
EP - 482
JO - CHANNELS
JF - CHANNELS
SN - 1933-6950
IS - 6
ER -
