KV 7 Channel Pharmacological Activation by the Novel Activator ML213: Role for Heteromeric KV 7.4/KV 7.5 Channels in Guinea Pig Detrusor Smooth Muscle Function

The Journal of Pharmacology and Experimental Therapeutics
Aaron ProvenceGeorgi V Petkov

Abstract

Voltage-gated KV7 channels (KV7.1 to KV7.5) are important regulators of the cell membrane potential in detrusor smooth muscle (DSM) of the urinary bladder. This study sought to further the current knowledge of KV7 channel function at the molecular, cellular, and tissue levels in combination with pharmacological tools. We used isometric DSM tension recordings, ratiometric fluorescence Ca2+ imaging, amphotericin-B perforated patch-clamp electrophysiology, and in situ proximity ligation assay (PLA) in combination with the novel compound N-(2,4,6-trimethylphenyl)-bicyclo[2.2.1]heptane-2-carboxamide (ML213), an activator of KV7.2, KV7.4, and KV7.5 channels, to examine their physiologic roles in guinea pig DSM function. ML213 caused a concentration-dependent (0.1-30 µM) inhibition of spontaneous phasic contractions in DSM isolated strips; effects blocked by the KV7 channel inhibitor XE991 (10 µM). ML213 (0.1-30 µM) also reduced pharmacologically induced and nerve-evoked contractions in DSM strips. Consistently, ML213 (10 µM) decreased global intracellular Ca2+ concentrations in Fura-2-loaded DSM isolated strips. Perforated patch-clamp electrophysiology revealed that ML213 (10 µM) caused an increase in the amplitude of whole-cell KV7 ...Continue Reading

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Citations

May 5, 2020·The Journal of General Physiology·Johan E LarssonSara I Liin
Jul 12, 2020·Epilepsia·Richard KanyoHarley T Kurata
Jul 7, 2020·American Journal of Physiology. Renal Physiology·John Malysz, Georgi V Petkov
Oct 3, 2019·American Journal of Physiology. Cell Physiology·Viktor YarotskyyGeorgi V Petkov
Dec 20, 2018·American Journal of Physiology. Cell Physiology·Viktor YarotskyyGeorgi V Petkov
Oct 13, 2020·Frontiers in Physiology·John Malysz, Georgi V Petkov
May 29, 2021·RSC Medicinal Chemistry·Matteo BorginiPeter Wipf
Mar 27, 2021·Brain : a Journal of Neurology·Isamu Aiba, Jeffrey L Noebels

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