{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,2]],"date-time":"2025-11-02T04:26:09Z","timestamp":1762057569917,"version":"build-2065373602"},"reference-count":64,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2022,6,24]],"date-time":"2022-06-24T00:00:00Z","timestamp":1656028800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology","doi-asserted-by":"publisher","award":["MOST-110-2320-B-006-028"],"award-info":[{"award-number":["MOST-110-2320-B-006-028"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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 \u03bcM, 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 \u03bcM). 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 \u03bcM) 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.<\/jats:p>","DOI":"10.3390\/ijms23137042","type":"journal-article","created":{"date-parts":[[2022,6,26]],"date-time":"2022-06-26T09:00:13Z","timestamp":1656234013000},"page":"7042","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["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)"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7821-9406","authenticated-orcid":false,"given":"Chao-Liang","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Medical Research, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi 60002, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Poyuan","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi 60002, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hsin-Yen","family":"Cho","sequence":"additional","affiliation":[{"name":"Department of Physiology, National Cheng Kung University Medical College, Tainan 70101, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tzu-Hsien","family":"Chuang","sequence":"additional","affiliation":[{"name":"Department of Physiology, National Cheng Kung University Medical College, Tainan 70101, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5208-3253","authenticated-orcid":false,"given":"Sheng-Nan","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Physiology, National Cheng Kung University Medical College, Tainan 70101, Taiwan"},{"name":"Institute of Basic Medical Sciences, National Cheng Kung University Medical College, Tainan 70101, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1016\/j.ejmech.2011.01.010","article-title":"Design, synthesis and biological activity of pyrazolo[1,5-a]pyrimidin-7(4H)-ones as novel Kv7\/KCNQ potassium channel activators","volume":"46","author":"Qi","year":"2011","journal-title":"Eur. J. Med. Chem."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1030","DOI":"10.1111\/j.1476-5381.2012.02232.x","article-title":"Modulation of K(v)7 potassium channels by a novel opener pyrazolo[1,5-a]pyrimidin-7(4H)-one compound QO-58","volume":"168","author":"Zhang","year":"2013","journal-title":"Br. J. Pharmacol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/j.ejps.2018.02.015","article-title":"Exploring in vivo metabolism and excretion of QO-58L using ultra-high-performance liquid chromatography coupled with tandem mass spectrometry","volume":"117","author":"Zhang","year":"2018","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1159\/000496422","article-title":"Suppression of KCNQ\/M Potassium Channel in Dorsal Root Ganglia Neurons Contributes to the Development of Osteoarthritic Pain","volume":"103","author":"Zhang","year":"2019","journal-title":"Pharmacology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1038\/aps.2016.33","article-title":"Activation of neuronal Kv7\/KCNQ\/M-channels by the opener QO58-lysine and its anti-nociceptive effects on inflammatory pain in rodents","volume":"37","author":"Teng","year":"2016","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_6","first-page":"1333","article-title":"Antinociceptive efficacy of QO-58 in the monosodium lodoacetate rat model for osteoarthritis pain","volume":"97","author":"Du","year":"2017","journal-title":"Zhonghua Yi Xue Za Zhi"},{"key":"ref_7","first-page":"574","article-title":"Pharmacokinetic study of QO-58: A new potassium channel opener","volume":"30","author":"Liu","year":"2014","journal-title":"Chin. Pharmacol. Bull."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1093\/cvr\/cvab031","article-title":"Impaired Kv7 channel activity in the central amygdala contributes to elevated sympathetic outflow in hypertension","volume":"118","author":"Sheng","year":"2022","journal-title":"Cardiovasc. Res."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Chang, W.T., and Wu, S.N. (2021). Effective Activation of BK(Ca) 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. Pharmaceuticals, 14.","DOI":"10.3390\/ph14050388"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1890","DOI":"10.1126\/science.282.5395.1890","article-title":"KCNQ2 and KCNQ3 potassium channel subunits: Molecular correlates of the M-channel","volume":"282","author":"Wang","year":"1998","journal-title":"Science"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1517\/14728222.7.6.737","article-title":"The therapeutic potential of neuronal KCNQ channel modulators","volume":"7","author":"Gribkoff","year":"2003","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1046\/j.1365-2826.2000.00447.x","article-title":"Expression of mRNA for voltage-dependent and inward-rectifying K channels in GH3\/B6 cells and rat pituitary","volume":"12","author":"Wulfsen","year":"2000","journal-title":"J. Neuroendocrinol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4614","DOI":"10.1523\/JNEUROSCI.0765-04.2004","article-title":"KCNQ\/M channels control spike afterdepolarization and burst generation in hippocampal neurons","volume":"24","author":"Yue","year":"2004","journal-title":"J. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1811","DOI":"10.1113\/jphysiol.2007.148304","article-title":"Regulation of neural KCNQ channels: Signalling pathways, structural motifs and functional implications","volume":"586","author":"Zaika","year":"2008","journal-title":"J. Physiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1111\/j.1476-5381.2009.00111.x","article-title":"Neural KCNQ (Kv7) channels","volume":"156","author":"Brown","year":"2009","journal-title":"Br. J. Pharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1007\/s00018-016-2359-y","article-title":"Modulation of Kv7 channels and excitability in the brain","volume":"74","author":"Greene","year":"2017","journal-title":"Cell Mol. Life Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1002\/hipo.22744","article-title":"Somatostatin depresses the excitability of subicular bursting cells: Roles of inward rectifier K+ channels, KCNQ channels and Epac","volume":"27","author":"Hu","year":"2017","journal-title":"Hippocampus"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.molcel.2020.10.037","article-title":"Structural Basis for the Modulation of Human KCNQ4 by Small-Molecule Drugs","volume":"81","author":"Li","year":"2021","journal-title":"Mol. Cell"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.neuroscience.2020.10.035","article-title":"Cholinergic Modulation of Membrane Properties of Calyx Terminals in the Vestibular Periphery","volume":"452","author":"Ramakrishna","year":"2021","journal-title":"Neuroscience"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"626470","DOI":"10.3389\/fphys.2021.626470","article-title":"KCNQ Current Contributes to Inspiratory Burst Termination in the Pre-B\u00f6tzinger Complex of Neonatal Rats in vitro","volume":"12","author":"Revill","year":"2021","journal-title":"Front. Physiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"453","DOI":"10.2174\/0929867053363045","article-title":"Recent developments on KCNQ potassium channel openers","volume":"12","author":"Wua","year":"2005","journal-title":"Curr. Med. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2576","DOI":"10.1021\/jm060989l","article-title":"Kv7 (KCNQ) channel modulators and neuropathic pain","volume":"50","author":"Munro","year":"2007","journal-title":"J. Med. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3953","DOI":"10.1113\/jphysiol.2012.235820","article-title":"M-type potassium channels modulate Schaffer collateral-CA1 glutamatergic synaptic transmission","volume":"590","author":"Sun","year":"2012","journal-title":"J. Physiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e99","DOI":"10.1111\/epi.12715","article-title":"The variable phenotypes of KCNQ-related epilepsy","volume":"55","author":"Allen","year":"2014","journal-title":"Epilepsia"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/aps.2015.131","article-title":"KCNQ potassium channels in sensory system and neural circuits","volume":"37","author":"Wang","year":"2015","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1146\/annurev-pharmtox-010617-052912","article-title":"KCNQ-Encoded Potassium Channels as Therapeutic Targets","volume":"58","author":"Barrese","year":"2018","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_27","first-page":"358","article-title":"Pharmacogenetics of KCNQ channel activation in 2 potassium channelopathy mouse models of epilepsy","volume":"59","author":"Gautier","year":"2017","journal-title":"Epilepsia"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3694","DOI":"10.1523\/JNEUROSCI.1914-19.2020","article-title":"M-Current Inhibition in Hippocampal Excitatory Neurons Triggers Intrinsic and Synaptic Homeostatic Responses at Different Temporal Scales","volume":"40","author":"Lezmy","year":"2020","journal-title":"J. Neurosci."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Cho, H.Y., Chuang, T.H., and Wu, S.N. (2021). The Effectiveness in Activating M-Type K+ Current Produced by Solifenacin ([(3R)-1-azabicyclo[2.2.2]octan-3-yl] (1S)-1-phenyl-3,4-dihydro-1H-isoquinoline-2-carboxylate): Independent of Its Antimuscarinic Action. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222212399"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Jones, F., Gamper, N., and Gao, H. (2021). Kv7 Channels and Excitability Disorders. Handbook of Experimental Pharmacology, Springer.","DOI":"10.1007\/164_2021_457"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Lo, Y.-C., Lin, C.-L., Fang, W.-Y., L\u0151rinczi, B., Szatm\u00e1ri, I., Chang, W.-H., F\u00fcl\u00f6p, F., and Wu, S.-N. (2021). Effective Activation by Kynurenic Acid and Its Aminoalkylated Derivatives on M-Type K+ Current. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22031300"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1007\/s40263-021-00885-y","article-title":"The Potential of KCNQ Potassium Channel Openers as Novel Antidepressants","volume":"36","author":"Costi","year":"2022","journal-title":"CNS Drugs"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"115821","DOI":"10.1016\/j.taap.2021.115821","article-title":"Development of KVO treatment strategies for chronic pain in a rat model of Gulf War Illness","volume":"434","author":"Flunker","year":"2021","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"eabh3021","DOI":"10.1126\/science.abh3021","article-title":"Hyperexcitable arousal circuits drive sleep instability during aging","volume":"375","author":"Li","year":"2022","journal-title":"Science"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"126603","DOI":"10.1016\/j.bmcl.2019.08.007","article-title":"Design and evaluation of pyrazolopyrimidines as KCNQ channel modulators","volume":"29","author":"Osuma","year":"2019","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1146\/annurev-pharmtox-052120-104249","article-title":"KCNQ Potassium Channels as Targets of Botanical Folk Medicines","volume":"62","author":"Redford","year":"2022","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"7742","DOI":"10.1523\/JNEUROSCI.19-18-07742.1999","article-title":"Two Types of K+ Channel Subunit, Erg1 and KCNQ2\/3, Contribute to the M-Like Current in a Mammalian Neuronal Cell","volume":"19","author":"Selyanko","year":"1999","journal-title":"J. Neurosci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.brainresbull.2019.03.016","article-title":"Concerted suppression of I(h) and activation of I(K(M)) by ivabradine, an HCN-channel inhibitor, in pituitary cells and hippocampal neurons","volume":"149","author":"Hsiao","year":"2019","journal-title":"Brain Res. Bull."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"173141","DOI":"10.1016\/j.ejphar.2020.173141","article-title":"Effectiveness in the inhibition of dapagliflozin and canagliflozin on M-type K+ current and \u03b1-methylglucoside-induced current in pituitary tumor (GH3) and pheochromocytoma PC12 cells","volume":"879","author":"So","year":"2020","journal-title":"Eur. J. Pharmacol."},{"key":"ref_40","first-page":"S163","article-title":"Airway Hydration, Apical K+ Secretion, and the Large-Conductance, Ca2+-activated and Voltage-dependent Potassium (BK) Channel","volume":"13","author":"Kis","year":"2016","journal-title":"Ann. Am. Thorac. Soc."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"181","DOI":"10.3389\/fnmol.2017.00181","article-title":"The Role of Kv7\/M Potassium Channels in Controlling Ectopic Firing in Nociceptors","volume":"10","author":"Barkai","year":"2017","journal-title":"Front. Mol. Neurosci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1152\/physrev.00001.2016","article-title":"Molecular Determinants of BK Channel Functional Diversity and Functioning","volume":"97","author":"Latorre","year":"2017","journal-title":"Physiol. Rev."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1007\/s40263-020-00706-8","article-title":"Targeting BK(Ca) Channels in Migraine: Rationale and Perspectives","volume":"34","author":"Gram","year":"2020","journal-title":"CNS Drugs"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Lu, T.L., Gao, Z.H., Li, S.W., and Wu, S.N. (2020). High Efficacy by GAL-021: A Known Intravenous Peripheral Chemoreceptor Modulator that Suppresses BK(Ca)-Channel Activity and Inhibits I(K(M)) or I(h). Biomolecules, 10.","DOI":"10.3390\/biom10020188"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"762175","DOI":"10.3389\/fphys.2021.762175","article-title":"BK Channel Gating Mechanisms: Progresses Toward a Better Understanding of Variants Linked Neurological Diseases","volume":"12","author":"Cui","year":"2021","journal-title":"Front. Physiol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2854","DOI":"10.1523\/JNEUROSCI.0192-20.2021","article-title":"BK Channel Regulation of Afterpotentials and Burst Firing in Cerebellar Purkinje Neurons","volume":"41","author":"Niday","year":"2021","journal-title":"J. Neurosci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1007\/s00424-003-1116-x","article-title":"Voltage-independent KCNQ4 currents induced by (+\/\u2212)BMS-204352","volume":"446","author":"Olesen","year":"2003","journal-title":"Pflug. Arch."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Hsu, H.T., Tseng, Y.T., Lo, Y.C., and Wu, S.N. (2014). Ability of naringenin, a bioflavonoid, to activate M-type potassium current in motor neuron-like cells and to increase BKCa-channel activity in HEK293T cells transfected with \u03b1-hSlo subunit. BMC Neurosci., 15.","DOI":"10.1186\/s12868-014-0135-1"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1668","DOI":"10.1523\/JNEUROSCI.16-05-01668.1996","article-title":"Characterization of an M-like current modulated by thyrotropin-releasing hormone in normal rat lactotrophs","volume":"16","author":"Sankaranarayanan","year":"1996","journal-title":"J. Neurosci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1111\/j.1582-4934.2004.tb00256.x","article-title":"Functions of erg K+ channels in excitable cells","volume":"8","author":"Schwarz","year":"2004","journal-title":"J. Cell Mol. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1393","DOI":"10.1152\/physrev.00036.2011","article-title":"hERG K+ channels: Structure, function, and clinical significance","volume":"92","author":"Vandenberg","year":"2012","journal-title":"Physiol. Rev."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"So, E.C., Foo, N.P., Ko, S.Y., and Wu, S.N. (2019). Bisoprolol, Known to Be a Selective \u03b21-Receptor Antagonist, Differentially but Directly Suppresses IK(M) and IK(erg) in Pituitary Cells and Hippocampal Neurons. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20030657"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1085\/jgp.200409130","article-title":"Hysteresis in the voltage dependence of HCN channels: Conversion between two modes affects pacemaker properties","volume":"125","author":"Pandey","year":"2005","journal-title":"J. Gen. Physiol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"14270","DOI":"10.1038\/srep14270","article-title":"Isoform dependent regulation of human HCN channels by cholesterol","volume":"5","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1016\/0028-3908(96)00135-9","article-title":"Regulation of M-type Potassium Channels in Mammalian Sympathetic Neurons: Action of Intracellular Calcium on Single Channel Currents","volume":"35","author":"Selyanko","year":"1996","journal-title":"Neuropharmacology"},{"key":"ref_56","first-page":"161","article-title":"Functional coupling of voltage-dependent L-type Ca2+ current to Ca2+-activated K+ current in pituitary GH3 cells","volume":"44","author":"Wu","year":"2001","journal-title":"Chin. J. Physiol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1152\/jn.00089.2021","article-title":"BK channel activation by L-type Ca2+ channels CaV1.2 and CaV1.3 during the subthreshold phase of an action potential","volume":"126","author":"Plante","year":"2021","journal-title":"J. Neurophysiol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"5819","DOI":"10.1021\/bi00185a021","article-title":"Tremorgenic Indole Alkaloids Potently Inhibit Smooth Muscle High-Conductance Calcium-Activated Potassium Channels","volume":"33","author":"Knaus","year":"1994","journal-title":"Biochemistry"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"3409","DOI":"10.1002\/jcp.25788","article-title":"Stimulatory actions of a novel thiourea derivative on large-conductance, calcium-activated potassium channels","volume":"232","author":"Wu","year":"2017","journal-title":"J. Cell. Physiol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.neuropharm.2016.11.024","article-title":"Acute stress diminishes M-current contributing to elevated activity of hypothalamic-pituitary-adrenal axis","volume":"114","author":"Zhou","year":"2016","journal-title":"Neuropharmacology"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1113\/JP275477","article-title":"Ether-\u00e0-go-go K+ channels: Effective modulators of neuronal excitability","volume":"596","author":"Bauer","year":"2018","journal-title":"J. Physiol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.3389\/fphar.2020.01091","article-title":"Evidence for the Effectiveness of Remdesivir (GS-5734), a Nucleoside-Analog Antiviral Drug in the Inhibition of IK(M) or IK(DR) and in the Stimulation of I (MEP)","volume":"11","author":"Bauer","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Chen, L., Cho, H.-Y., Chuang, T.-H., Ke, T.-L., and Wu, S.-N. (2022). The Effectiveness of Isoplumbagin and Plumbagin in Regulating Amplitude, Gating Kinetics, and Voltage-Dependent Hysteresis of erg-mediated K+ Currents. Biomedicines, 10.","DOI":"10.3390\/biomedicines10040780"},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Hung, T.-Y., Wu, S.-N., and Huang, C.-W. (2021). The Integrated Effects of Brivaracetam, a Selective Analog of Levetiracetam, on Ionic Currents and Neuronal Excitability. Biomedicines, 9.","DOI":"10.3390\/biomedicines9040369"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/13\/7042\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:39:44Z","timestamp":1760139584000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/13\/7042"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,24]]},"references-count":64,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2022,7]]}},"alternative-id":["ijms23137042"],"URL":"https:\/\/doi.org\/10.3390\/ijms23137042","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2022,6,24]]}}}