Effective Activation of BKCa Channels by QO-40 (5-(Chloromethyl)-3-(Naphthalen-1-yl)-2-(Trifluoromethyl)Pyrazolo [1,5-a]pyrimidin-7(4H)-one), Known to Be an Opener of KCNQ2/Q3 Channels

Abstract

QO-40 (5-(chloromethyl)-3-(naphthalene-1-yl)-2-(trifluoromethyl) pyrazolo[1,5-a]pyrimidin-7(4H)-one) is a novel and selective activator of KCNQ2/KCNQ3 K+ channels. However, it remains largely unknown whether this compound can modify any other type of plasmalemmal ionic channel. The effects of QO-40 on ion channels in pituitary GH3 lactotrophs were investigated in this study. QO-40 stimulated Ca2+-activated K+ current (IK(Ca)) with an EC50 value of 2.3 μM in these cells. QO-40-stimulated IK(Ca) was attenuated by the further addition of GAL-021 or paxilline but not by linopirdine or TRAM-34. In inside-out mode, this compound added to the intracellular leaflet of the detached patches stimulated large-conductance Ca2+-activated K+ (BKCa) channels with no change in single-channel conductance; however, there was a decrease in the slow component of the mean closed time of BKCa channels. The KD value required for the QO-40-mediated decrease in the slow component at the mean closure time was 1.96 μM. This compound shifted the steady-state activation curve of BKCa channels to a less positive voltage and decreased the gating charge of the channel. The application of QO-40 also increased the hysteretic strength of BKCa channels elicited by a long-lasting isosceles-triangular ramp voltage. In HEK293T cells expressing α-hSlo, QO-40 stimulated BKCa channel activity. Overall, these findings demonstrate that QO-40 can interact directly with the BKCa channel to increase the amplitude of IK(Ca) in GH3 cells.

Evidence for Dual Activation of IK(M) and IK(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)

“…Several small molecules (e.g., BMS-204352, naringenin, and QO-40) that demonstrated to stimulate K M -channel activity have been reportedly noted to regulate other types of K + currents (e.g., I K(Ca) ) [9,47,48]. For these reasons, we next explored if QO-58 is able to modify the amplitude of I K(Ca) residing in GH 3 cells.…”

“…The ameliorating effects of this compound have been viewed to be closely linked to its activation of KCNQ (K V 7) channels [4,7,8]. However, QO-40 (5-(chloromethyl)-3-(nathphalen-1-yl)-2-(trifluoromethyl)pyrazolo [1,5-a]pyrimidin-7(4H)-one), a compound structurally similar to QO-58, has been noticeably reported to stimulate the activity of largeconductance Ca 2+ -activated K + (BK Ca ) channels [9]. Therefore, whether and to what extent QO-58 is able to modify the amplitude or gating kinetics on different types of membrane ion currents remain to be not thoroughly explored.…”

“…The regulation of such activity can play essential roles in various physiological or pathophysiological events, such as membrane excitability, neurotransmitter release, stimulus-secretion coupling, muscle relaxation, and pain sensation [40][41][42][43][44][45][46]. Moreover, some small molecules, such as BMS-204352, naringenin and QO-40, have been reported to activate I K(M) as well as to enhance the activity of BK Ca channels in excitable cells [9,47,48].…”