Evidence for Dual Activation of I K(M) and I K(Ca) Caused by QO-58 (5-(2,6-Dichloro-5-fluoropyridin-3-yl)-3-phenyl-2-(trifluoromethyl)-1H-pyrazolol[1,5-a]pyrimidin-7-one).

QO-58 (5-(2,6-dichloro-5-fluoropyridin-3-yl)-3-phenyl-2-(trifluoromethyl)-1H-pyrazolol[1,5-a]pyrimidin-7-one) has been regarded to be an activator of K V 7 channels with analgesic properties. However, whether and how the presence of this compound can result in any modifications of other types of membrane ion channels in native cells are not thoroughly investigated. In this study, we investigated its perturbations on M-type K + current ( I K(M) ), Ca 2+ -activated K + current ( I K(Ca) ), large-conductance Ca 2+ -activated K + (BK Ca ) channels, and erg -mediated K + current ( I K(erg) ) identified from pituitary tumor (GH 3 ) cells. Addition of QO-58 can increase the amplitude of I K(M) and I K(Ca) in a concentration-dependent fashion, with effective EC 50 of 3.1 and 4.2 μM, respectively. This compound could shift the activation curve of I K(M) toward a leftward direction with being void of changes in the gating charge. The strength in voltage-dependent hysteresis (V hys ) of I K(M) evoked by upright triangular ramp pulse (V ramp ) was enhanced by adding QO-58. The probabilities of M-type K + (K M ) channels that will be open increased upon the exposure to QO-58, although no modification in single-channel conductance was seen. Furthermore, GH 3 -cell exposure to QO-58 effectively increased the amplitude of I K(Ca) as well as enhanced the activity of BK Ca channels. Under inside-out configuration, QO-58, applied at the cytosolic leaflet of the channel, activated BK Ca -channel activity, and its increase could be attenuated by further addition of verruculogen, but not by linopirdine (10 μM). The application of QO-58 could lead to a leftward shift in the activation curve of BK Ca channels with neither change in the gating charge nor in single-channel conductance. Moreover, cell exposure of QO-58 (10 μM) resulted in a minor suppression of I K(erg) amplitude in response to membrane hyperpolarization. The docking results also revealed that there are possible interactions of the QO-58 molecule with the KCNQ or K Ca 1.1 channel. Overall, dual activation of I K(M) and I K(Ca) caused by the presence of QO-58 eventually may have high impacts on the functional activity (e.g., anti-nociceptive effect) residing in electrically excitable cells. Care must be exercised when interpreting data generated with QO-58 as it is not entirely KCNQ/K V 7 selective.