TY - JOUR
T1 - Biophysical characterization of KV3.1 potassium channel activating compounds
AU - Taskin, Bahar
AU - von Schoubye, Nadia Lybøl
AU - Sheykhzade, Majid
AU - Bastlund, Jesper Frank
AU - Grunnet, Morten
AU - Jespersen, Thomas
N1 - Copyright © 2015 Elsevier B.V. All rights reserved.
PY - 2015/7/5
Y1 - 2015/7/5
N2 - The effect of two positive modulators, RE1 and EX15, on the voltage-gated K+ channel Kv3.1 was investigated using the whole-cell patch-clamp technique on HEK293 cells expressing Kv3.1a. RE1 and EX15 increased the Kv3.1 currents in a concentration-dependent manner with an EC50 value of 4.5 and 1.3 μM, respectively. However, high compound concentrations caused an inhibition of the Kv3.1 current. The compound-induced activation of Kv3.1 channels showed a profound hyperpolarized shift in activation kinetics. 30 μM RE1 shifted V1/2 from 5.63±0.31 mV to -9.71±1.00 mV and 10 μM EX15 induced a shift from 10.77±0.32 mV to -15.11±1.57 mV. The activation time constant (Tauact) was reduced for both RE1 and EX15, with RE1 being the fastest activator. The deactivation time constant (Taudeact) was also markedly reduced for both RE1 and EX15, with EX15 inducing the most prominent effect. Furthermore, subjected to depolarizing pulses at 30 Hz, both compounds were showing a use-dependent effect resulting in a reduction of the compound-mediated effect. However, during these conditions, RE1- and EX15-modified current amplitudes still exceeded the control condition amplitudes by up to 200%. In summary, the present study introduces the first detailed biophysical characterization of two new Kv3.1 channel modifying compounds with different modulating properties.
AB - The effect of two positive modulators, RE1 and EX15, on the voltage-gated K+ channel Kv3.1 was investigated using the whole-cell patch-clamp technique on HEK293 cells expressing Kv3.1a. RE1 and EX15 increased the Kv3.1 currents in a concentration-dependent manner with an EC50 value of 4.5 and 1.3 μM, respectively. However, high compound concentrations caused an inhibition of the Kv3.1 current. The compound-induced activation of Kv3.1 channels showed a profound hyperpolarized shift in activation kinetics. 30 μM RE1 shifted V1/2 from 5.63±0.31 mV to -9.71±1.00 mV and 10 μM EX15 induced a shift from 10.77±0.32 mV to -15.11±1.57 mV. The activation time constant (Tauact) was reduced for both RE1 and EX15, with RE1 being the fastest activator. The deactivation time constant (Taudeact) was also markedly reduced for both RE1 and EX15, with EX15 inducing the most prominent effect. Furthermore, subjected to depolarizing pulses at 30 Hz, both compounds were showing a use-dependent effect resulting in a reduction of the compound-mediated effect. However, during these conditions, RE1- and EX15-modified current amplitudes still exceeded the control condition amplitudes by up to 200%. In summary, the present study introduces the first detailed biophysical characterization of two new Kv3.1 channel modifying compounds with different modulating properties.
U2 - 10.1016/j.ejphar.2015.03.061
DO - 10.1016/j.ejphar.2015.03.061
M3 - Journal article
C2 - 25845309
SN - 0014-2999
VL - 758
SP - 164
EP - 170
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
ER -