Potassium Channel Openers: The Case of BK Channel Activators

Nardi, Antônio Egídio; Calderone, Vincenzo; Olesen, Sp

doi:10.2174/157018006776743242

Cited by 18 publications

(16 citation statements)

References 75 publications

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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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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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“…[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.…”

Section: Main Textmentioning

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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“…Thus, in cardiovascular diseases BK Ca channel modulation may have therapeutic benefits. BK Ca blockers (Shieh et al 2007) may possibly constrict a dilated blood vessel whereas BK Ca openers (Nardi et al 2006) could dilate a constricted blood vessel as observed in the treatment of stroke. Dilatation of cerebral blood vessels is believed to be involved during a migraine attack (Ray and Wolff 1940) together with activation of the neurovascular pain pathway (Edvinsson and Uddman 2005;Goadsby et al 2002;Silberstein 2004).…”

Section: Introductionmentioning

confidence: 99%

Molecular investigations of BKCa channels and the modulatory β-subunits in porcine basilar and middle cerebral arteries

et al. 2009

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Large conductance calcium-activated potassium (BK(Ca)) channels are fundamental in the regulation of cerebral vascular basal tone. We investigated the expression of the mRNA transcripts for the BK(Ca) channel and its modulatory beta-subunits (beta1-beta4) in porcine basilar and middle cerebral arteries using reverse transcription polymerase chain reaction (RT-PCR) and quantitative real-time PCR. Western blotting was used to detect immunoreactivity for the porcine BK(Ca) channel alpha-subunit and beta-subunit proteins. The BK(Ca) channel alpha-subunit RNA and protein distribution patterns were visualized using in situ hybridization and immunofluorescence studies, respectively. The study verified that the BK(Ca) channel alpha-subunit is located to smooth muscle cells of porcine basilar and middle cerebral arteries. The mRNA transcript for beta1-, beta2- and beta4-subunit were shown by RT-PCR in porcine basilar and middle cerebral arteries. However, at the protein level, only, the beta1-subunit protein was found by western blotting.

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Potassium Channel Openers: The Case of BK Channel Activators

Cited by 18 publications

References 75 publications

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

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

Molecular investigations of BKCa channels and the modulatory β-subunits in porcine basilar and middle cerebral arteries

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Potassium Channel Openers: The Case of BK Channel Activators

Cited by 18 publications

References 75 publications

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

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

Molecular investigations of BKCa channels and the modulatory β-subunits in porcine basilar and middle cerebral arteries

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