Modulation of the Ca 2+ -dependent K + Channel, hslo , by the Substituted Diphenylurea NS 1608, Paxilline and Internal Ca 2+

Strøbæk, Dorte; Christophersen, Palle; Holm, Ninna R.; Moldt, P.; Ahring, Philip K.; Johansen, Teit E.; Olesen, Søren‐Peter

doi:10.1016/0028-3908(96)00096-2

Cited by 77 publications

(40 citation statements)

References 46 publications

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“…The fact that the potentiation of KCa1.1 current by NS11021 decreases with increasing concentrations of Ca 2ϩ has also been found for another KCa1.1 activator, diCl-DHAA (Sakamoto et al, 2006), whereas the opposite holds true for BMS-204352, when whole-cell current amplitudes were examined (Gribkoff et al, 2001). NS11021 belongs to the group of KCa1.1 channel openers, which include NS1608 (Strøbaek et al, 1996), mallotoxin (Zakharov et al, 2005), and KB130015 (Gessner et al, 2007) that activates KCa1.1 channels in the absence of Ca 2ϩ . At 1 M, NS11021 shifts the V 0.5 by approximately 30 mV in a hyperpolarizing direction, which resembles the effect of 1 M tamoxifen (Dick et al, 2001), whereas NS1619 shifts V 0.5 Ϫ70 mV but at a 30-fold higher concentration (Olesen et al, 1994).…”

Section: Discussionmentioning

confidence: 77%

The Small Molecule NS11021 Is a Potent and Specific Activator of Ca2+-Activated Big-Conductance K+ Channels

Bentzen

Nardi²,

Calloe³

et al. 2007

Molecular Pharmacology

112

111

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Section: Discussionmentioning

confidence: 77%

The Small Molecule NS11021 Is a Potent and Specific Activator of Ca2+-Activated Big-Conductance K+ Channels

Bentzen

Nardi²,

Calloe³

et al. 2007

Molecular Pharmacology

112

111

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“…These results suggest that BK channel activators could represent a novel therapeutic approach for treating overactive bladder. However, despite the development of a large number of BK channel openers over the last two decades (23)(24)(25)(26)(27)(28)(29), they have failed to progress through clinical trials, because they showed poor efficacy, presumably due to their lack of effect at physiological membrane potentials, combined with a reduction in BK channels in patients with overactive bladder (30).…”

Section: +mentioning

confidence: 99%

Molecular mechanisms underlying the effect of the novel BK channel opener GoSlo: Involvement of the S4/S5 linker and the S6 segment

Webb

Kshatri

Large

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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GoSlo-SR-5-6 is a novel large-conductance Ca 2+ -activated K + (BK) channel agonist that shifts the activation V 1/2 of these channels in excess of −100 mV when applied at a concentration of 10 μM. Although the structure-activity relationship of this family of molecules has been established, little is known about how they open BK channels. To help address this, we used a combination of electrophysiology, mutagenesis, and mathematical modeling to investigate the molecular mechanisms underlying the effect of GoSlo-SR-5-6. Our data demonstrate that the effects of this agonist are practically abolished when three point mutations are made: L227A in the S4/S5 linker in combination with S317R and I326A in the S6C region. Our data suggest that GoSlo-SR-5-6 interacts with the transmembrane domain of the channel to enhance pore opening. The Horrigan-Aldrich model suggests that GoSlo-SR-5-6 works by stabilizing the open conformation of the channel and the activated state of the voltage sensors, yet decouples the voltage sensors from the pore gate.

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“…To illustrate how efficacious the GoSlo-SR family of compounds were, we compared the effects of two well established BK channel openers, NS1619 [21] and NS11021 [12] on these currents. Figure 5A shows a typical example in which we applied NS1619 (orange line) at a concentration of 10 µM, to a patch containing approximately 23 BK channels.…”

Section: Structure Activity Relationship (Sar)mentioning

confidence: 99%

“…This was not significantly different to the results obtained with 5k and suggests that although 5r was more efficacious than 5k, there was little difference in the potency of these two compounds on BK channels. Interestingly, the slope of the concentration effect curve for 5r (mean Hill slope 1.8; 95% Confidence Intervals 1.2 to 2.5) was steeper than for 5k (mean Hill slope 0.9; 95% Confidence Intervals 0.4 to 1.3), perhaps suggesting that there was a change in the extent of cooperativity of the binding sites when 5r was applied.To illustrate how efficacious the GoSlo-SR family of compounds were, we compared the effects of two well established BK channel openers, NS1619 [21] and NS11021 [12] on these currents. Figure 5A shows a typical example in which we applied NS1619 (orange line) at a concentration of 10 µM, to a patch containing approximately 23 BK channels.…”

mentioning

confidence: 99%

Structure–Activity Relationships of a Novel Group of Large‐Conductance Ca²⁺‐Activated K⁺ (BK) Channel Modulators: The GoSlo‐SR Family

et al. 2012

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Main TextLarge-conductance Ca 2+ -activated K + (BK) channels contribute to the repolarisation or hyperpolarisation of a wide variety of tissues including bladder and urethral smooth muscles. [1][2][3] In bladder smooth muscle, BK channels are activated by both the influx of Ca 2+ across the membrane and the release of Ca 2+ from intracellular stores and are responsible for the rapid repolarisation phase of the action potential. Thus, BK channels help limit the excitability of bladder smooth muscle and consequently reduce its contractile behaviour.Meredith et al., [4] elegantly illustrated the importance of BK channels in controlling bladder contractility by demonstrating that mutant mice, which lack the BKα subunits, have overactive bladders and are functionally incontinent.It is clear from the above studies that BK channels offer a promising target for the treatment of urinary incontinence caused by overactive bladder (OAB). In this study, we have synthesised a new family of BK channel openers, termed the GoSlo-SR family, that may form scaffold molecules for future development in the treatment of this disease. The predominant cause of OAB is the uncontrolled, inappropriate contraction of the bladder smooth muscle, which increases intravesicle pressure above urethral closure pressure causing urine leakage. [5] The current 'gold standard' therapeutic treatment (anticholinergics) for overactive bladder has compliance rates of <30%, due to unwanted side effects including chronic constipation and dry mouth. [6] Consequently, the pharmaceutical industry has invested significantly in trying to target smooth muscle function by developing novel BK channel modulators to help treat disorders such as urinary incontinence. [6][7][8][9][10] Although a large number of chemically diverse BK channel openers have already been developed, [8,9] only a few studies [11][12][13] have focused on examining the effects of these compounds across a wide voltage range to include physiological potentials (~−100 mV to 0 mV). [10][11][12] Instead, the majority of studies have focused on the ability of compounds to open channels only at potentials some 50 to 100 mV more positive than a cell is ever likely to encounter in vivo. It appears that the majority of BK channel openers developed to date would have little effect at physiological membrane potentials and this may explain their poor efficacy in clinical trials [7] and subsequent failure to progress to market.In this study, we have examined the effects of the GoSlo-SR family of molecules across a wide range of potentials (from −100 mV to +150 mV). In addition, we have chosen to measure efficacy of these BK channel openers by calculating the shift in the voltage required to half maximally activate the channels (ΔV1/2). We have previously used this approach to demonstrate that 10 µM Cibacron Blue (Reactive Blue 2, RB2, see Figure 1A) activated BK channels recorded from bladder smooth muscle cells with ΔV1/2 of~−50 mV. [11] However, little is known about the minimal structure necessary to ret...

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Modulation of the Ca 2+ -dependent K + Channel, hslo , by the Substituted Diphenylurea NS 1608, Paxilline and Internal Ca 2+

Cited by 77 publications

References 46 publications

The Small Molecule NS11021 Is a Potent and Specific Activator of Ca2+-Activated Big-Conductance K+ Channels

The Small Molecule NS11021 Is a Potent and Specific Activator of Ca2+-Activated Big-Conductance K+ Channels

Molecular mechanisms underlying the effect of the novel BK channel opener GoSlo: Involvement of the S4/S5 linker and the S6 segment

Structure–Activity Relationships of a Novel Group of Large‐Conductance Ca²⁺‐Activated K⁺ (BK) Channel Modulators: The GoSlo‐SR Family

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Modulation of the Ca 2+ -dependent K + Channel, hslo , by the Substituted Diphenylurea NS 1608, Paxilline and Internal Ca 2+

Cited by 77 publications

References 46 publications

The Small Molecule NS11021 Is a Potent and Specific Activator of Ca2+-Activated Big-Conductance K+ Channels

The Small Molecule NS11021 Is a Potent and Specific Activator of Ca2+-Activated Big-Conductance K+ Channels

Molecular mechanisms underlying the effect of the novel BK channel opener GoSlo: Involvement of the S4/S5 linker and the S6 segment

Structure–Activity Relationships of a Novel Group of Large‐Conductance Ca2+‐Activated K+ (BK) Channel Modulators: The GoSlo‐SR Family

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Structure–Activity Relationships of a Novel Group of Large‐Conductance Ca²⁺‐Activated K⁺ (BK) Channel Modulators: The GoSlo‐SR Family