Expression and function of the small-conductance Ca2+-activated K+ channel is decreased in urinary bladder smooth muscle cells from female guinea pig with partial bladder outlet obstruction

Li, Ning; Ding, Honglin; He, Xiaoning; Li, Zizheng; Liu, Yili

doi:10.1007/s11255-017-1592-0

Cited by 10 publications

(12 citation statements)

References 35 publications

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“…SK channels have a more dominant role in regulating DSM excitability, such that apamin abolishes the fast hyperpolarizations [ 20 , 39 , 82 , 83 , 84 , 85 ]. For I SK channel modeling, the parameters are adopted from guinea-pig urinary bladder smooth muscle [ 40 ].…”

Section: Results I: Modeling Of Dsm Cell Ion Channelsmentioning

confidence: 99%

“…In part, these uncertainties stem from the fact that any particular K + channel blocker may influence the permeability of not just one but two or more of the K + conductances present. According to Soder et al 2013 [ 84 ], Parajuli et al 2012 [ 71 ] and Li et al 2017 [ 39 ], elevated conductance of SK channels hyperpolarizes the RMP of DSM cells. Likewise, recent documents ascribed the hyperpolarization in murine DSM cells to SK channels, although the latter were postulated to be present in neighboring electrically connected interstitial cells, not in the DSM itself.…”

Section: Discussionmentioning

confidence: 99%

“…In this regard, some of the reported effects of pharmacological maneuvers on DSM cell electrophysiology have raised some open biological questions and engendered conflicting hypotheses regarding the precise roles of the K + ion channels in modulating shape of action potentials. For example, according to Li et al, 2017 [ 39 ], the elevated conductance of small-conductance calcium-dependent potassium channels (SK) hyperpolarizes the resting membrane potential (RMP) of DSM cells. However, according to Herrera et al, 2002 [ 40 ], SK channels modulate the after-hyperpolarization period of the spike in the DSM cells.…”

Section: Introductionmentioning

confidence: 99%

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A biophysically constrained computational model of the action potential of mouse urinary bladder smooth muscle

2018

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Urinary incontinence is associated with enhanced spontaneous phasic contractions of the detrusor smooth muscle (DSM). Although a complete understanding of the etiology of these spontaneous contractions is not yet established, it is suggested that the spontaneously evoked action potentials (sAPs) in DSM cells initiate and modulate the contractions. In order to further our understanding of the ionic mechanisms underlying sAP generation, we present here a biophysically detailed computational model of a single DSM cell. First, we constructed mathematical models for nine ion channels found in DSM cells based on published experimental data: two voltage gated Ca2+ ion channels, an hyperpolarization-activated ion channel, two voltage-gated K+ ion channels, three Ca2+-activated K+ ion channels and a non-specific background leak ion channel. The ion channels’ kinetics were characterized in terms of maximal conductances and differential equations based on voltage or calcium-dependent activation and inactivation. All ion channel models were validated by comparing the simulated currents and current-voltage relations with those reported in experimental work. Incorporating these channels, our DSM model is capable of reproducing experimentally recorded spike-type sAPs of varying configurations, ranging from sAPs displaying after-hyperpolarizations to sAPs displaying after-depolarizations. The contributions of the principal ion channels to spike generation and configuration were also investigated as a means of mimicking the effects of selected pharmacological agents on DSM cell excitability. Additionally, the features of propagation of an AP along a length of electrically continuous smooth muscle tissue were investigated. To date, a biophysically detailed computational model does not exist for DSM cells. Our model, constrained heavily by physiological data, provides a powerful tool to investigate the ionic mechanisms underlying the genesis of DSM electrical activity, which can further shed light on certain aspects of urinary bladder function and dysfunction.

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Section: Results I: Modeling Of Dsm Cell Ion Channelsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A biophysically constrained computational model of the action potential of mouse urinary bladder smooth muscle

2018

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“…We investigated if UCL 1684 relaxation of smooth muscle also acted on other known cholinergic responsive (bladder) or cholinergic non-responsive (vascular) smooth muscle (Herrera and Nelson, 2002;Thorneloe et al, 2008;Li et al, 2017). Pretreatment with UCL 1684 partially inhibited relaxation of bladder contraction ( Figure 4A, top panel, summarized in 4B), and caused little inhibition of phenylephrine-evoked contraction of vascular (aortic) rings (summarized in Figure 4B).…”

Section: Inhibition Of Smooth Muscle Contractionmentioning

confidence: 99%

Bis-Quinolinium Cyclophane Blockers of SK Potassium Channels Are Antagonists of M3 Muscarinic Acetylcholine Receptors

et al. 2020

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Dequalinium is used as an antimicrobial compound for oral health and other microbial infections. Derivatives of dequalinium, the bis-quinolinium cyclophanes UCL 1684 and UCL 1848, are high affinity SK potassium channel antagonists. Here we investigated these compounds as M3 muscarinic receptor (mACHR) antagonists. We used the R-CEPIAer endoplasmic reticulum calcium reporter to functionally assay for Gq-coupled receptor signaling, and investigated the bis-quinolinium cyclophanes as antagonists of M3 mACHR activation in transfected CHO cells. Given mACHR roles in airway smooth muscle (ASM) contractility, we also tested the ability of UCL 1684 to relax ASM. We find that these compounds antagonized M3 mACHRs with an IC 50 of 0.27 mM for dequalinium chloride, 1.5 mM for UCL 1684 and 1.0 mM for UCL 1848. UCL 1684 also antagonized M1 (IC 50 0.12 mM) and M5 (IC 50 0.52 mM) mACHR responses. UCL 1684 was determined to be a competitive antagonist at M3 receptors as it increased the EC 50 for carbachol without a reduction in the maximum response. The Ki for UCL1684 determined from competition binding experiments was 909 nM. UCL 1684 reduced carbachol-evoked ASM contractions (>90%, IC 50 0.43 mM), and calcium mobilization in rodent and human lung ASM cells. We conclude that dequalinium and bis-quinolinium cyclophanes antagonized M3 mACHR activation at sub-to low micromolar concentrations, with UCL 1684 acting as an ASM relaxant. Caution should be taken when using these compounds to block SK potassium channels, as inhibition of mACHRs may be a side-effect if excessive concentrations are used.

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“…Moreover, OAB is associated with increased DSM excitability, contractility and spontaneous phasic contractions. Therefore, changes in the expression and function of DSM regulatory proteins may alter the contractility of the DSM [12–14].…”

Section: Introductionmentioning

confidence: 99%

Attenuated BK channel function promotes overactive bladder in a rat model of obesity

Ding

Zhang

et al. 2019

Aging

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Overactive bladder (OAB) is mostly observed in obese individuals, and is associated with enhanced excitability and contractility of the detrusor smooth muscle (DSM). Large-conductance voltage- and Ca2+-activated K+ (BK) channels reduce the excitability and contractility of the DSM. We tested whether obesity-induced OAB is associated with altered BK channel expression and activity in the DSM. Seven-week-old female Sprague-Dawley rats (N=80) were fed a normal or high-fat diet (HFD) for 12 weeks. HFD-fed rats exhibited a higher average bodyweight and urodynamically established detrusor overactivity. mRNA levels of the Kcnma1 (BKα subunit) and Kcnmb1 (BKβ1 subunit) in whole tissues and cells from the DSM were reduced in HFD-fed rats. A selective BK channel opener, NS1619, was then applied to DSM cells from the two groups of rats. Patch-clamp techniques revealed that spontaneous transient outward currents, NS1619-induced activation of spontaneous transient outward currents, and whole-cell BK currents, as well as NS1619-induced membrane hyperpolarization, were attenuated in DSM cells from HFD-fed rats. The relaxation effect of NS1619 on contractility was reduced in DSM strips from HFD-fed rats. Thus, impaired expression of Kcnma1 and Kcnmb1 in the DSM contributes to obesity-induced OAB, suggesting that BK channels could be a useful treatment targets in OAB.

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Expression and function of the small-conductance Ca2+-activated K+ channel is decreased in urinary bladder smooth muscle cells from female guinea pig with partial bladder outlet obstruction

Abstract: The attenuated expression and function of SK channels, which results in the increased UBSM cells excitability and contributes to DO, was discovered in PBOO UBSM cells, suggesting that SK channels might be potential therapeutic targets for the control of OAB.

Cited by 10 publications

References 35 publications

A biophysically constrained computational model of the action potential of mouse urinary bladder smooth muscle

A biophysically constrained computational model of the action potential of mouse urinary bladder smooth muscle

Bis-Quinolinium Cyclophane Blockers of SK Potassium Channels Are Antagonists of M3 Muscarinic Acetylcholine Receptors

Attenuated BK channel function promotes overactive bladder in a rat model of obesity

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