Development of KVO treatment strategies for chronic pain in a rat model of Gulf War Illness

Flunker, L.D.; Nutter, T.J.; Bowers, Claudia M.; Cooper, Brian Y.

doi:10.1016/j.taap.2021.115821

Cited by 2 publications

(2 citation statements)

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“…The QO-58-stimulated BK Ca channel activity was also effectively counteracted by subsequent addition of verruculogen (1 µM), yet not by linopirdine (10 µM). Verruculogen is known to block BK Ca channels effectively [58,59], while linopirdine can suppress K M -channel activity [18,31,33]. Under such scenario, it is plausible to notice that apart from its effects on I K(M) , QO-58-stimulated I K(Ca) arises primarily through the observed activation of BK Ca channels, although the precise or detailed ionic mechanism of QO-58 actions on the activity and gating kinetics of BK Ca channels remains to be resolved.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, targeting I K(M) has been growingly thought to be an adjunctive regimen for the management of varying neurological, smooth muscle, or endocrine disorders which are closely linked to membrane hyperexcitability. These disorders include neuropathic pain and epilepsy [4,11,19,[21][22][23][24][25][26][27][28][29][30][31][32][33][34]. A series of pyrazolopyrimidines or several botanical folk medicines have been also recently demonstrated to be KCNQ channel modulators [35,36].…”

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confidence: 99%

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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)

Cho

et al. 2022

IJMS

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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 KV7 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 (IK(M)), Ca2+-activated K+ current (IK(Ca)), large-conductance Ca2+-activated K+ (BKCa) channels, and erg-mediated K+ current (IK(erg)) identified from pituitary tumor (GH3) cells. Addition of QO-58 can increase the amplitude of IK(M) and IK(Ca) in a concentration-dependent fashion, with effective EC50 of 3.1 and 4.2 μM, respectively. This compound could shift the activation curve of IK(M) toward a leftward direction with being void of changes in the gating charge. The strength in voltage-dependent hysteresis (Vhys) of IK(M) evoked by upright triangular ramp pulse (Vramp) was enhanced by adding QO-58. The probabilities of M-type K+ (KM) channels that will be open increased upon the exposure to QO-58, although no modification in single-channel conductance was seen. Furthermore, GH3-cell exposure to QO-58 effectively increased the amplitude of IK(Ca) as well as enhanced the activity of BKCa channels. Under inside-out configuration, QO-58, applied at the cytosolic leaflet of the channel, activated BKCa-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 BKCa 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 IK(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 KCa1.1 channel. Overall, dual activation of IK(M) and IK(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/KV7 selective.

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