KCNQ4 channel activation by BMS-204352 and retigabine
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KCNQ4 channel activation by BMS-204352 and retigabine. / Schrøder, Rikke Louise K.; Jespersen, Thomas; Christophersen, P; Strøbaek, D; Jensen, B S; Olesen, S P.
In: Neuropharmacology, Vol. 40, No. 7, 01.06.2001, p. 888-98.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - KCNQ4 channel activation by BMS-204352 and retigabine
AU - Schrøder, Rikke Louise K.
AU - Jespersen, Thomas
AU - Christophersen, P
AU - Strøbaek, D
AU - Jensen, B S
AU - Olesen, S P
PY - 2001/6/1
Y1 - 2001/6/1
N2 - Activation of potassium channels generally reduces cellular excitability, making potassium channel openers potential drug candidates for the treatment of diseases related to hyperexcitabilty such as epilepsy, neuropathic pain, and neurodegeneration. Two compounds, BMS-204352 and retigabine, presently in clinical trials for the treatment of stroke and epilepsy, respectively, have been proposed to exert their protective action via an activation of potassium channels. Here we show that KCNQ4 channels, stably expressed in HEK293 cells, were activated by retigabine and BMS-204352 in a reversible and concentration-dependent manner in the concentration range 0.1-10 microM. Both compounds shifted the KCNQ4 channel activation curves towards more negative potentials by about 10 mV. Further, the maximal current obtainable at large positive voltages was also increased concentration-dependently by both compounds. Finally, a pronounced slowing of the deactivation kinetics was induced in particular by BMS-204352. The M-current blocker linopirdine inhibited the baseline current, as well as the BMS-204352-induced activation of the KCNQ4 channels. KCNQ2, KCNQ2/Q3, and KCNQ3/Q4 channels were activated to a similar degree as KCNQ4 channels by 10 microM of BMS-204352 and retigabine, respectively. The compounds are, thus, likely to be general activators of M-like currents.
AB - Activation of potassium channels generally reduces cellular excitability, making potassium channel openers potential drug candidates for the treatment of diseases related to hyperexcitabilty such as epilepsy, neuropathic pain, and neurodegeneration. Two compounds, BMS-204352 and retigabine, presently in clinical trials for the treatment of stroke and epilepsy, respectively, have been proposed to exert their protective action via an activation of potassium channels. Here we show that KCNQ4 channels, stably expressed in HEK293 cells, were activated by retigabine and BMS-204352 in a reversible and concentration-dependent manner in the concentration range 0.1-10 microM. Both compounds shifted the KCNQ4 channel activation curves towards more negative potentials by about 10 mV. Further, the maximal current obtainable at large positive voltages was also increased concentration-dependently by both compounds. Finally, a pronounced slowing of the deactivation kinetics was induced in particular by BMS-204352. The M-current blocker linopirdine inhibited the baseline current, as well as the BMS-204352-induced activation of the KCNQ4 channels. KCNQ2, KCNQ2/Q3, and KCNQ3/Q4 channels were activated to a similar degree as KCNQ4 channels by 10 microM of BMS-204352 and retigabine, respectively. The compounds are, thus, likely to be general activators of M-like currents.
KW - Anticonvulsants
KW - Carbamates
KW - Cell Line
KW - Dose-Response Relationship, Drug
KW - Humans
KW - Indoles
KW - KCNQ Potassium Channels
KW - Phenylenediamines
KW - Potassium Channels
KW - Potassium Channels, Voltage-Gated
M3 - Journal article
C2 - 11378159
VL - 40
SP - 888
EP - 898
JO - Neuropharmacology
JF - Neuropharmacology
SN - 0028-3908
IS - 7
ER -
ID: 33018256