scholarly journals Regulation of urinary bladder smooth muscle contractions by ryanodine receptors and BK and SK channels

2000 ◽  
Vol 279 (1) ◽  
pp. R60-R68 ◽  
Author(s):  
Gerald M. Herrera ◽  
Thomas J. Heppner ◽  
Mark T. Nelson
Keyword(s):  
Smooth Muscle ◽  
Urinary Bladder ◽  
Negative Feedback ◽  
Ryanodine Receptors ◽  
Bk Channels ◽  
Sk Channels ◽  
Bladder Smooth Muscle ◽  
Contraction Amplitude ◽  
Contraction Frequency ◽  
Urinary Bladder Smooth Muscle

This study examines the roles of voltage-dependent Ca2+ channels (VDCC), ryanodine receptors (RyRs), large-conductance Ca2+-activated K+ (BK) channels, and small-conductance Ca2+-activated K+ (SK) channels in the regulation of phasic contractions of guinea pig urinary bladder smooth muscle (UBSM). Nisoldipine (100 nM), a dihydropyridine inhibitor of VDCC, abolished spontaneous UBSM contractions. Ryanodine (10 μM) increased contraction frequency and thereby integrated force and, in the presence of the SK blocker apamin, had a greater effect on integrated force than ryanodine alone. Blocking BK (iberiotoxin, 100 nM) or SK (apamin, 100 nM) channels increased contraction amplitude and duration but decreased frequency. The contractile response to iberiotoxin was more pronounced than to apamin. The increases in contraction amplitude and duration to apamin were substantially augmented with ryanodine pretreatment. These results indicate that BK and SK channels have prominent roles as negative feedback elements to limit UBSM contraction amplitude and duration. RyRs also appear to play a significant role as a negative feedback regulator of contraction frequency and duration, and this role is influenced by the activity of SK channels.

Differential regulation of Ca2+-activated K+ channels by β-adrenoceptors in guinea pig urinary bladder smooth muscle

2005 ◽  
Vol 288 (6) ◽  
pp. C1255-C1263 ◽  
Author(s):  
Georgi V. Petkov ◽  
Mark T. Nelson
Keyword(s):  
Smooth Muscle ◽  
Steady State ◽  
Urinary Bladder ◽  
Ryanodine Receptors ◽  
Bk Channels ◽  
Bk Channel ◽  
Bladder Smooth Muscle ◽  
Cellular Mechanisms ◽  
Open Probability ◽  
Urinary Bladder Smooth Muscle

Stimulation of β-adrenoceptors contributes to the relaxation of urinary bladder smooth muscle (UBSM) through activation of large-conductance Ca2+-activated K+ (BK) channels. We examined the mechanisms by which β-adrenoceptor stimulation leads to an elevation of the activity of BK channels in UBSM. Depolarization from −70 to +10 mV evokes an inward L-type dihydropyridine-sensitive voltage-dependent Ca2+ channel (VDCC) current, followed by outward steady-state and transient BK current. In the presence of ryanodine, which blocks the transient BK currents, isoproterenol, a nonselective β-adrenoceptor agonist, increased the VDCC current by ∼25% and the steady-state BK current by ∼30%. In the presence of the BK channel inhibitor iberiotoxin, isoproterenol did not cause activation of the remaining steady-state K+ current component. Decreasing Ca2+ influx through VDCC by nifedipine or depolarization to +80 mV suppressed the isoproterenol-induced activation of the steady-state BK current. Unlike forskolin, isoproterenol did not change significantly the open probability of single BK channels in the absence of Ca2+ sparks and with VDCC inhibited by nifedipine. Isoproterenol elevated Ca2+ spark (local intracellular Ca2+ release through ryanodine receptors of the sarcoplasmic reticulum) frequency and associated transient BK currents by ∼1.4-fold. The data support the concept that in UBSM β-adrenoceptor stimulation activates BK channels by elevating Ca2+ influx through VDCC and by increasing Ca2+ sparks, but not through a Ca2+-independent mechanism. This study reveals key regulatory molecular and cellular mechanisms of β-adrenergic regulation of BK channels in UBSM that could provide new targets for drugs in the treatment of bladder dysfunction.

Negative feedback regulation of nerve-mediated contractions by KCa channels in mouse urinary bladder smooth muscle

2005 ◽  
Vol 289 (2) ◽  
pp. R402-R409 ◽  
Author(s):  
Gerald M. Herrera ◽  
Bud Etherton ◽  
Bernhard Nausch ◽  
Mark T. Nelson
Keyword(s):  
Smooth Muscle ◽  
Urinary Bladder ◽  
Negative Feedback ◽  
Nerve Stimulation ◽  
Bk Channels ◽  
Bladder Smooth Muscle ◽  
Parasympathetic Nerves ◽  
Sk Channel ◽  
Urinary Bladder Smooth Muscle ◽  
Evoked Contractions

When the urinary bladder is full, activation of parasympathetic nerves causes release of neurotransmitters that induce forceful contraction of the detrusor muscle, leading to urine voiding. The roles of ion channels that regulate contractility of urinary bladder smooth muscle (UBSM) in response to activation of parasympathetic nerves are not well known. The present study was designed to characterize the role of large (BK)- and small-conductance (SK) Ca2+-activated K+ (KCa) channels in regulating UBSM contractility in response to physiological levels of nerve stimulation in UBSM strips from mice. Nerve-evoked contractions were induced by electric field stimulation (0.5–50 Hz) in isolated strips of UBSM. BK and SK channel inhibition substantially increased the amplitude of nerve-evoked contractions up to 2.45 ± 0.12- and 2.99 ± 0.25-fold, respectively. When both SK and BK channels were inhibited, the combined response was additive. Inhibition of L-type voltage-dependent Ca2+ channels (VDCCs) in UBSM inhibited nerve-evoked contractions by 92.3 ± 2.0%. These results suggest that SK and BK channels are part of two distinct negative feedback pathways that limit UBSM contractility in response to nerve stimulation by modulating the activity of VDCCs. Dysfunctional regulation of UBSM contractility by alterations in BK/SK channel expression or function may underlie pathologies such as overactive bladder.

scholarly journals Stimulation of β3-adrenoceptors relaxes rat urinary bladder smooth muscle via activation of the large-conductance Ca2+-activated K+ channels

2008 ◽  
Vol 295 (5) ◽  
pp. C1344-C1353 ◽  
Author(s):  
Kiril L. Hristov ◽  
Xiangli Cui ◽  
Sean M. Brown ◽  
Lei Liu ◽  
Whitney F. Kellett ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Urinary Bladder ◽  
Bk Channels ◽  
Bk Channel ◽  
Bladder Smooth Muscle ◽  
Rat Urinary Bladder ◽  
Urinary Bladder Smooth Muscle ◽  
Brl 37344 ◽  
Stimulation Of

We investigated the role of large-conductance Ca2+-activated K+ (BK) channels in β3-adrenoceptor (β3-AR)-induced relaxation in rat urinary bladder smooth muscle (UBSM). BRL 37344, a specific β3-AR agonist, inhibits spontaneous contractions of isolated UBSM strips. SR59230A, a specific β3-AR antagonist, and H89, a PKA inhibitor, reduced the inhibitory effect of BRL 37344. Iberiotoxin, a specific BK channel inhibitor, shifts the BRL 37344 concentration response curves for contraction amplitude, net muscle force, and tone to the right. Freshly dispersed UBSM cells and the perforated mode of the patch-clamp technique were used to determine further the role of β3-AR stimulation by BRL 37344 on BK channel activity. BRL 37344 increased spontaneous, transient, outward BK current (STOC) frequency by 46.0 ± 20.1%. In whole cell mode at a holding potential of Vh = 0 mV, the single BK channel amplitude was 5.17 ± 0.28 pA, whereas in the presence of BRL 37344, it was 5.55 ± 0.41 pA. The BK channel open probability was also unchanged. In the presence of ryanodine and nifedipine, the current-voltage relationship in response to depolarization steps in the presence and absence of BRL 37344 was identical. In current-clamp mode, BRL 37344 caused membrane potential hyperpolarization from −26.1 ± 2.1 mV (control) to −29.0 ± 2.2 mV. The BRL 37344-induced hyperpolarization was eliminated by application of iberiotoxin, tetraethylammonium or ryanodine. The data indicate that stimulation of β3-AR relaxes rat UBSM by increasing the BK channel STOC frequency, which causes membrane hyperpolarization and thus relaxation.

scholarly journals Frequency encoding of cholinergic- and purinergic-mediated signaling to mouse urinary bladder smooth muscle: modulation by BK channels

2007 ◽  
Vol 292 (1) ◽  
pp. R616-R624 ◽  
Author(s):  
Matthias E. Werner ◽  
Anna-Maria Knorn ◽  
Andrea L. Meredith ◽  
Richard W. Aldrich ◽  
Mark T. Nelson
Keyword(s):  
Smooth Muscle ◽  
Urinary Bladder ◽  
Bk Channels ◽  
Bk Channel ◽  
Detrusor Muscle ◽  
Wild Type ◽  
Bladder Smooth Muscle ◽  
Overactive Detrusor ◽  
Maximal Force ◽  
Urinary Bladder Smooth Muscle

In the urinary bladder, contractions of the detrusor muscle and urine voiding are induced by the neurotransmitters ACh and ATP, released from parasympathetic nerves. Activation of K+ channels, in particular the large-conductance Ca2+-activated K+ (BK) channels, opposes increases in excitability and contractility of urinary bladder smooth muscle (UBSM). We have shown that deleting the gene mSlo1 in mice ( Slo−/−), encoding the BK channel, leads to enhanced nerve-mediated and neurotransmitter-dependent contractility of UBSM ( 38 ). Here, we examine the location of the BK channel in urinary bladder strips from mouse. Immunohistochemical analysis revealed that the channel is expressed in UBSM but not in nerves that innervate the smooth muscle. The relationship between electrical field stimulation and force generation of the cholinergic and purinergic pathways was examined by applying blockers of the respective receptors in UBSM strips from wild-type and from Slo−/− (knockout) mice. In wild-type strips, the stimulation frequency required to obtain a half-maximal force was significantly lower for the purinergic (7.2 ± 0.3 Hz) than the cholinergic pathway (19.1 ± 1.5 Hz), whereas the maximum force was similar. Blocking BK channels with iberiotoxin or ablation of the Slo gene increased cholinergic- and purinergic-mediated force at low frequencies, i.e., significantly decreased the frequency for a half-maximal force. Our results indicate that the BK channel has a very significant role in reducing both cholinergic- and purinergic-induced contractility and suggest that alterations in BK channel expression or function could contribute to pathologies such as overactive detrusor.

scholarly journals Constitutive PKA activity is essential for maintaining the excitability and contractility in guinea pig urinary bladder smooth muscle: role of the BK channel

2014 ◽  
Vol 307 (12) ◽  
pp. C1142-C1150 ◽  
Author(s):  
Wenkuan Xin ◽  
Ning Li ◽  
Qiuping Cheng ◽  
Vitor S. Fernandes ◽  
Georgi V. Petkov
Keyword(s):  
Smooth Muscle ◽  
Urinary Bladder ◽  
Fluorescence Microscopy ◽  
Guinea Pig ◽  
Bk Channels ◽  
Bk Channel ◽  
Bladder Smooth Muscle ◽  
Ratiometric Fluorescence ◽  
Urinary Bladder Smooth Muscle

The elevation of protein kinase A (PKA) activity activates the large-conductance voltage- and Ca2+-activated K+ (BK) channels in urinary bladder smooth muscle (UBSM) cells and consequently attenuates spontaneous phasic contractions of UBSM. However, the role of constitutive PKA activity in UBSM function has not been studied. Here, we tested the hypothesis that constitutive PKA activity is essential for controlling the excitability and contractility of UBSM. We used patch clamp electrophysiology, line-scanning confocal and ratiometric fluorescence microscopy on freshly isolated guinea pig UBSM cells, and isometric tension recordings on freshly isolated UBSM strips. Pharmacological inhibition of the constitutive PKA activity with H-89 or PKI 14–22 significantly reduced the frequency and amplitude of spontaneous transient BK channel currents (TBKCs) in UBSM cells. Confocal and ratiometric fluorescence microscopy studies revealed that inhibition of constitutive PKA activity with H-89 reduced the frequency and amplitude of the localized Ca2+ sparks but increased global Ca2+ levels and the magnitude of Ca2+ oscillations in UBSM cells. H-89 abolished the spontaneous transient membrane hyperpolarizations and depolarized the membrane potential in UBSM cells. Inhibition of PKA with H-89 or KT-5720 also increased the amplitude and muscle force of UBSM spontaneous phasic contractions. This study reveals the novel concept that constitutive PKA activity is essential for controlling localized Ca2+ signals generated by intracellular Ca2+ stores and cytosolic Ca2+ levels. Furthermore, constitutive PKA activity is critical for mediating the spontaneous TBKCs in UBSM cells, where it plays a key role in regulating spontaneous phasic contractions in UBSM.

scholarly journals BK channel activation by NS11021 decreases excitability and contractility of urinary bladder smooth muscle

2010 ◽  
Vol 298 (2) ◽  
pp. R378-R384 ◽  
Author(s):  
Jeffrey J. Layne ◽  
Bernhard Nausch ◽  
Søren-Peter Olesen ◽  
Mark T. Nelson
Keyword(s):  
Smooth Muscle ◽  
Urinary Bladder ◽  
Action Potentials ◽  
Bk Channels ◽  
Bk Channel ◽  
Bladder Smooth Muscle ◽  
Open Probability ◽  
Urinary Bladder Smooth Muscle ◽  
Spontaneous Action ◽  
Spontaneous Action Potentials

Large-conductance Ca2+-activated potassium (BK) channels play an important role in regulating the function and activity of urinary bladder smooth muscle (UBSM), and the loss of BK channel function has been shown to increase UBSM excitability and contractility. However, it is not known whether activation of BK channels has the converse effect of reducing UBSM excitability and contractility. Here, we have sought to investigate this possibility by using the novel BK channel opener NS11021. NS11021 (3 μM) caused an approximately threefold increase in both single BK channel open probability ( Po) and whole cell BK channel currents. The frequency of spontaneous action potentials in UBSM strips was reduced by NS11021 from a control value of 20.9 ± 5.9 to 10.9 ± 3.7 per minute. NS11021 also reduced the force of UBSM spontaneous phasic contractions by ∼50%, and this force reduction was blocked by pretreatment with the BK channel blocker iberiotoxin. NS11021 (3 μM) had no effect on contractions evoked by nerve stimulation. These findings indicate that activating BK channels reduces the force of UBSM spontaneous phasic contractions, principally through decreasing the frequency of spontaneous action potentials.

scholarly journals NFATc3 regulates BK channel function in murine urinary bladder smooth muscle

2008 ◽  
Vol 295 (3) ◽  
pp. C611-C623 ◽  
Author(s):  
JJ Layne ◽  
ME Werner ◽  
DC Hill-Eubanks ◽  
MT Nelson
Keyword(s):  
Transcription Factor ◽  
Smooth Muscle ◽  
Urinary Bladder ◽  
Bk Channels ◽  
Bk Channel ◽  
Wild Type ◽  
Bladder Smooth Muscle ◽  
Activated T Cells ◽  
Α Subunit ◽  
Urinary Bladder Smooth Muscle

The nuclear factor of activated T-cells (NFAT) is a Ca2+-dependent transcription factor that has been reported to regulate the expression of smooth muscle contractile proteins and ion channels. Here we report that large conductance Ca2+-sensitive potassium (BK) channels and voltage-gated K+ (KV) channels may be regulatory targets of NFATc3 in urinary bladder smooth muscle (UBSM). UBSM myocytes from NFATc3-null mice displayed a reduction in iberiotoxin (IBTX)-sensitive BK currents, a decrease in mRNA for the pore-forming α-subunit of the BK channel, and a reduction in BK channel density compared with myocytes from wild-type mice. Tetraethylammonium chloride-sensitive KV currents were elevated in UBSM myocytes from NFATc3-null mice, as was mRNA for the Shab family member KV2.1. Despite KV current upregulation, bladder strips from NFATc3-null mice displayed an elevated contractile response to electrical field stimulation relative to strips from wild-type mice, but this difference was abrogated in the presence of the BK channel blocker IBTX. These results support a role for the transcription factor NFATc3 in regulating UBSM contractility, primarily through an NFATc3-dependent increase in BK channel activity.

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