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

• Main Authors: Wei-Ting Chang, Sheng-Nan Wu
• Format: Article
• Language: English
• Published: MDPI AG 2021-04-01
• Series: Pharmaceuticals
• Subjects: OQ-40 (5-(chloromethyl)-3-(naphthalene-1-yl)-2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-7-(4<i>H</i>)-one); Ca²⁺-activated K⁺ current; large-conductance Ca²⁺-activated K⁺ channel; single-channel kinetics; hysteresis
• Online Access: https://www.mdpi.com/1424-8247/14/5/388

QO-40 (5-(chloromethyl)-3-(naphthalene-1-yl)-2-(trifluoromethyl) pyrazolo[1,5-a]pyrimidin-7(4<i>H</i>)-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 (<i>I</i>_K(Ca)) with an EC₅₀ value of 2.3 μM in these cells. QO-40-stimulated <i>I</i>_K(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⁺ (BK_Ca) channels with no change in single-channel conductance; however, there was a decrease in the slow component of the mean closed time of BK_Ca channels. The <i>K</i>_D 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 BK_Ca 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 BK_Ca channels elicited by a long-lasting isosceles-triangular ramp voltage. In HEK293T cells expressing <i>α-hSlo</i>, QO-40 stimulated BK_Ca channel activity. Overall, these findings demonstrate that QO-40 can interact directly with the BK_Ca channel to increase the amplitude of <i>I</i>_K(Ca) in GH₃ cells.