Detrusor Smooth Muscle KV7 Channels: Emerging New Regulators of Urinary Bladder Function

Abstract

Relaxation and contraction of the urinary bladder smooth muscle, also known as the detrusor smooth muscle (DSM), facilitate the micturition cycle. DSM contractility depends on cell excitability, which is established by the synchronized activity of multiple diverse ion channels. K + channels, the largest family of channels, control DSM excitability by maintaining the resting membrane potential and shaping the action potentials that cause the phasic contractions. Among the members of the voltage-gated K + (K V) channel superfamily, K V type 7 (K V 7) channels-K V 7.1-K V 7.5 members encoded by KCNQ1-KCNQ5 genes-have been recently identified as functional regulators in various cell types including vascular, cardiac, and neuronal cells. Their regulatory roles in DSM, however, are just now emerging and remain to be elucidated. To address this gap, our research group has initiated the systematic investigation of human DSM K V 7 channels in collaboration with clinical urologists. In this comprehensive review, we summarize the current understanding of DSM Kv7 channels and highlight recent discoveries in the field. We describe K V 7 channel expression profiles at the mRNA and protein levels, and further elaborate on functional effects of K V 7 channel selective modulators on DSM excitability, contractility, and intracellular Ca 2+ dynamics in animal species along with in vivo studies and the limited data on human DSM. Within each topic, we highlight the main observations, current gaps in knowledge, and most pressing questions and concepts in need of resolution. We emphasize the lack of systematic studies on human DSM K V 7 channels that are now actively ongoing in our laboratory.

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

“…It is worth noting that different types of smooth muscle cells, including smooth myocytes of the urinary bladder, have been demonstrated to be functionally expressed in the activity of K M (KCNQx) channels [52,53,[78][79][80][81][82][83][84][85][86][87][88][89]. The SOL-induced interaction with K M channels to modify the magnitude and gating of I K(M) has the propensity to change muscarinic cholinergic activation involved in the micturition reflex, presuming that the in vivo results happen.…”

XEN1101: A Novel Potassium Channel Modulator for the Potential Treatment of Focal Epilepsy in Adults

“…This possible adverse event should be monitored in future studies: voltage-gated K+ channels regulate the bladder detrusor smooth muscle function and ezogabine-produced urinary retention in rodents but had minimal effects in humans. 18 At baseline, the subject's median seizure frequency was ~13 per month (28 days). 16,17 During the study treatment, participants in the 25 mg, 20 mg, 10 mg and placebo groups had a median percentage change in monthly seizure frequency of 52.8%, 46.4%, 33.3% and 18.2%, respectively.…”

Selective KCNQ2/3 Potassium Channel Opener ICA-069673 Inhibits Excitability in Mouse Vagal Sensory Neurons

“…Although K V 7.2 and K V 7.3 subunits are mainly expressed in the nervous system, K V 7.4 and K V 7.5 are also abundantly expressed in non-neuronal tissues. In fact, K V 7.4 and K V 7.5 are the major K V 7 subunits in smooth muscles of vasculature and hollow visceral organs where they regulate the smooth muscle contractility and vascular tone (Jepps et al, 2013;Malysz and Petkov, 2020), and in skeletal muscle where they regulate the proliferation, differentiation and muscle force development (Schroeder et al, 2000;Iannotti et al, 2013;Zagorchev et al, 2016). Opening K V 7.4 or K V 7.4/7.5 channels in these tissues likely contributes to the common side effects of retigabine, such as urinary retention, asthenia and symptomatic hypotension.…”