Characteristics of Ca2+ release for activation of K+ current and contractile system in some smooth muscles

Imaizumi, Yuji; Henmi, Satoshi; Uyama, Yoshiaki; Atsuki, Kaoru; Torii, Y.; Ohizumi, Yasushi; Watanabe, Minoru

doi:10.1152/ajpcell.1996.271.3.c772

Cited by 31 publications

(32 citation statements)

References 22 publications

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“…We observed local transient increases in Ca 2ϩ in UBSM cells from both Slo ϩ/ϩ and Slo Ϫ/Ϫ mice (Fig. 5, B and C), with spatial and temporal characteristics consistent with calcium sparks described previously (10,17,29,30,32). Furthermore, Ca 2ϩ spark amplitude and frequency were not different between Slo ϩ/ϩ and Slo Ϫ/Ϫ UBSM cells (Fig.…”

Section: Resultssupporting

confidence: 87%

Overactive Bladder and Incontinence in the Absence of the BK Large Conductance Ca2+-activated K+ Channel

Meredith

Thorneloe

Werner

et al. 2004

Journal of Biological Chemistry

311

363

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BK large conductance voltage-and calcium-activated potassium channels respond to elevations in intracellular calcium and membrane potential depolarization, braking excitability of smooth muscle. BK channels are thought to have a particularly prominent role in urinary bladder smooth muscle function and therefore are candidate targets for overactive bladder therapy. To address the role of the BK channel in urinary bladder function, the gene mSlo1 for the pore-forming subunit of the BK channel was deleted. Slo ؊/؊ mice were viable but exhibited moderate ataxia. Urinary bladder smooth muscle cells of Slo ؊/؊ mice lacked calcium-and voltageactivated BK currents, whereas local calcium transients ("calcium sparks") and voltage-dependent potassium currents were unaffected. In the absence of BK channels, urinary bladder spontaneous and nerve-evoked contractions were greatly enhanced. Consistent with increased urinary bladder contractility caused by the absence of BK currents, Slo ؊/؊ mice demonstrate a marked elevation in urination frequency. These results reveal a central role for BK channels in urinary bladder function and indicate that BK channel dysfunction leads to overactive bladder and urinary incontinence.Overactive urinary bladder and urinary incontinence is a significant health issue occurring in about 51 million (ϳ17%) of the United States population (1), frequently occurring as a secondary consequence of conditions such as diabetes mellitus, stroke, and spinal cord injury. Urge incontinence is caused by overactivity of the urinary bladder smooth muscle (UBSM), 1 often a result of partial urethral outlet obstruction that can occur during prostate hypertrophy. Currently there is a lack of effective therapeutic agents to control urinary bladder function. Antimuscarinic agents, which impair UBSM contraction, are used to treat urinary incontinence but have limited effectiveness and undesirable side effects. More recently, potassium channel opening drugs have been explored as therapeutic agents for urinary incontinence (2-6).BK potassium channels regulate membrane potential and repolarization of UBSM action potentials (7-8). UBSM BK channels are activated by membrane potential depolarization and calcium influx through voltage-dependent calcium channels that occur during the action potential (9). UBSM BK channels are also activated by local intracellular calcium release through ryanodine receptors (calcium sparks) (10). Specific inhibition of BK channels by iberiotoxin (IBTX) causes a pronounced elevation in bladder contractility (8,(11)(12). Deletion of the smooth muscle-specific, modulatory ␤1 subunit decreases the apparent voltage-and calcium-sensitivity of UBSM BK channels, leading to an enhancement of phasic contractility (12). These studies point to a pivotal role of the BK channel in urinary bladder function. EXPERIMENTAL PROCEDURESGeneration of Slo Ϫ/Ϫ Mice-mSlo1 genomic clones were isolated from a 129/SvJ BAC library (Incyte Genomics) using an ϳ1.6-kb EcoRV/XhoI cDNA probe fragment. A 7.8-kb SalI/BamHI geno...

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Section: Resultssupporting

confidence: 87%

Overactive Bladder and Incontinence in the Absence of the BK Large Conductance Ca2+-activated K+ Channel

Meredith

Thorneloe

Werner

et al. 2004

Journal of Biological Chemistry

311

363

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“…Upon depolarization to 0 mV the transient outward current reached a peak within 20 ms of the start of the depolarization. Similar currents were observed in urinary bladder myocytes (Imaizumi et al 1996b). The time to the peak of global F intensity at 0 mV over the whole image was 78·8 ± 6·0 ms in vas deferens cells (n = 18) and 63·5 ± 1·1 ms in urinary bladder cells (n = 13) but the outward current peaked within 15·0 ± 0·8 ms (n = 18) in vas deferens and 16·3 ± 0·8 ms (n = 13) in urinary bladder cells.…”

Section: Resultssupporting

confidence: 70%

“…Similar results with 50-100 ìÒ Cd¥ or 10 ìÒ verapamil were obtained in three vas deferens cells and two urinary bladder cells. The outward current, but not the hot spots, was inhibited by 1-2 mÒ TEA or 30-100 nÒ iberiotoxin (IbTX); the decreases in peak outward current by Cd¥, TEA or IbTX were 86 ± 5, 79 ± 6 and 67 ± 7 %, respectively, in vas deferens myocytes (n = 5, 8 and 5), which were similar to the decreases in urinary bladder myocytes (Imaizumi et al 1996b). Addition of 10 mÒ EGTA to the pipette solution markedly reduced the outward current (n = 4).…”

Section: Resultsmentioning

confidence: 59%

“…Series resistance was between 4 and 8 MÙ and was partly compensated. Data were stored and analysed using menu-drive software as previously reported (Imaizumi et al 1996b). Membrane currents were digitized using a pulse code modulation (PCM) recording system (PCM_501ES; Sony, Tokyo, Japan) which was modified to give a frequency response from DC to 20 kHz and stored on videotape.…”

Section: Cell Isolationmentioning

confidence: 99%

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Ca²⁺ images and K⁺ current during depolarization in smooth muscle cells of the guinea‐pig vas deferens and urinary bladder

Imaizumi

Torii

Ohi

et al. 1998

The Journal of Physiology

118

134

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Electrical events and intracellular calcium concentration ([Ca2+]) imaged using fluo‐3 and laser scanning confocal microscopy were simultaneously monitored in single smooth muscle cells freshly isolated from guinea‐pig vas deferens or urinary bladder. Images obtained every 8 ms, during stepping from ‐60 to 0 or +10 mV for 50 ms under voltage clamp, showed that a rise in [Ca2+] could be detected within 20 ms of depolarization in five to twenty small (< 2 μm diameter) ‘hot spots’, over 95 % of which were located within 1.5 μm of the cell membrane. Depolarization at 30 s intervals activated hot spots at the same places. Cd2+ or verapamil abolished both hot spots and Ca2+‐activated K+ current (IK,Ca). Caffeine almost abolished hot spots and markedly reduced IK,Ca. Cyclopiazonic acid, which raised basal global [Ca2+], decreased the rise in hot spot [Ca2+] and IK,Ca amplitude during depolarization. These results suggest that Ca2+ entry caused Ca2+‐induced Ca2+ release (CICR). Under voltage clamp, hot spot [Ca2+] closely paralleled the rise in IK,Ca and reached a peak within 20 ms of the start of depolarization, but the rise in global [Ca2+] over the whole cell area was much slower. Step depolarization to potentials positive to ‐20 mV caused hot spots to grow in size and coalesce, leading to a rise in global [Ca2+] and contraction. Ca2+ hot spots also occurred during the up‐stroke of an evoked action potential under current clamp. It is concluded that the entry of Ca2+ in the early stages of an action potential evokes CICR from discrete subplasmalemma Ca2+ storage sites and generates hot spots that spread to initiate a contraction. The activation of Ca2+‐dependent K+ channels in the plasmalemma over hot spots initiates IK,Ca and action potential repolarization.

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“…[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.…”

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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Characteristics of Ca2+ release for activation of K+ current and contractile system in some smooth muscles

Cited by 31 publications

References 22 publications

Overactive Bladder and Incontinence in the Absence of the BK Large Conductance Ca2+-activated K+ Channel

Overactive Bladder and Incontinence in the Absence of the BK Large Conductance Ca2+-activated K+ Channel

Ca²⁺ images and K⁺ current during depolarization in smooth muscle cells of the guinea‐pig vas deferens and urinary bladder

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

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Characteristics of Ca2+ release for activation of K+ current and contractile system in some smooth muscles

Cited by 31 publications

References 22 publications

Overactive Bladder and Incontinence in the Absence of the BK Large Conductance Ca2+-activated K+ Channel

Overactive Bladder and Incontinence in the Absence of the BK Large Conductance Ca2+-activated K+ Channel

Ca2+ images and K+ current during depolarization in smooth muscle cells of the guinea‐pig vas deferens and urinary bladder

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

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Ca²⁺ images and K⁺ current during depolarization in smooth muscle cells of the guinea‐pig vas deferens and urinary bladder

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