Local Ca<sup>2+</sup> transients and distribution of BK channels and ryanodine receptors in smooth muscle cells of guinea‐pig vas deferens and urinary bladder

Ohi, Yoshiaki; Yamamura, Hisao; Nagano, Norihiro; Ohya, Susumu; Muraki, Katsuhiko; Watanabe, Minoru; Imaizumi, Yuji

doi:10.1111/j.1469-7793.2001.t01-3-00313.x

Cited by 100 publications

(119 citation statements)

References 43 publications

(58 reference statements)

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“…The Ca 2ϩ sparks recorded under control conditions in the present study are similar to those previously reported for guinea pig vas deferens (25) and other smooth muscles (14). Blockade of the IP 3 channel with either 2-APB or heparin produced a significant increase in spark frequency (Figs.…”

Section: Discussionsupporting

confidence: 79%

Inositol 1,4,5-trisphosphate receptors modulate Ca²⁺ sparks and Ca²⁺ store content in vas deferens myocytes

White

McGeown

2003

American Journal of Physiology-Cell Physiology

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White, Carl, and J. Graham McGeown. Inositol 1,4,5-trisphosphate receptors modulate Ca 2ϩ sparks and Ca 2ϩ store content in vas deferens myocytes. Am J Physiol Cell Physiol 285: C195-C204, 2003. First published March 5, 2003 10.1152/ajpcell.00374.2002 sparks were observed in fluo 4-loaded myocytes from guinea pig vas deferens with line-scan confocal imaging. They were abolished by ryanodine (100 M), but the inositol 1,4,5-trisphosphate (IP 3) receptor (IP3R) blockers 2-aminoethoxydiphenyl borate (2-APB; 100 M) and intracellular heparin (5 mg/ml) increased spark frequency, rise time, duration, and spread. Very prolonged Ca 2ϩ release events were also observed in ϳ20% of cells treated with IP 3R blockers but not under control conditions. 2-APB and heparin abolished norepinephrine (10 M; 0 Ca 2ϩ )-evoked Ca 2ϩ transients but increased caffeine (10 mM; 0 Ca 2ϩ ) transients in fura 2-loaded myocytes. Transients evoked by ionomycin (25 M; 0 Ca 2ϩ ) were also enhanced by 2-APB. Ca 2ϩ sparks and transients evoked by norepinephrine and caffeine were abolished by thimerosal (100 M), which sensitizes the IP 3R to IP3. In cells voltage clamped at Ϫ40 mV, spontaneous transient outward currents (STOCs) were increased in frequency, amplitude, and duration in the presence of 2-APB. These data are consistent with a model in which the Ca 2ϩ store content in smooth muscle is limited by tonic release of Ca 2ϩ via an IP3-dependent pathway. Blockade of IP 3Rs elevates sarcoplasmic reticulum store content, promoting Ca 2ϩ sparks and STOC activity. calcium ion release; calcium ion transients; smooth muscle IT IS WELL ESTABLISHED THAT release of Ca 2ϩ from the sarcoplasmic reticulum (SR) can be evoked by activating receptors sensitive to inositol 1,4,5-trisphosphate (IP 3 Rs) or ryanodine (RyRs) (2). The resulting Ca 2ϩ signal may be generalized or restricted to a specific region of the cell. Transient, local release events known as "Ca 2ϩ sparks" are generated by the spontaneous opening of a cluster of RyR channels (3, 15). These sparks represent fundamental signaling events whose spatial and temporal summation generates global increases in intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ) during excitation-contraction coupling in cardiac and skeletal muscle (6,29). In smooth muscle sparks may also modulate membrane conductances (for review see Ref. 14), either opening Ca 2ϩ -activated Cl Ϫ channels to cause depolarization and contraction (40) or promoting relaxation by activating large-conductance Ca 2ϩ -activated K ϩ channels and so hyperpolarizing the membrane (24, 41). Understanding the control of Ca 2ϩ spark activity is crucial, therefore, to our understanding of smooth muscle function.The [Ca 2ϩ ] within the cytosol and the SR lumen may both play an important role in spark modulation. An elevation in [Ca 2ϩ ] i increases the open probability of the RyR channel, increasing the frequency of Ca 2ϩ sparks (7), whereas changes in the SR load can affect both spark frequency and amplitude (41). The filling state of the SR must reflect...

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Section: Discussionsupporting

confidence: 79%

Inositol 1,4,5-trisphosphate receptors modulate Ca²⁺ sparks and Ca²⁺ store content in vas deferens myocytes

White

McGeown

2003

American Journal of Physiology-Cell Physiology

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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: 62%

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

310

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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“…1,2 Many electrophysiological and functional studies have been performed to identify and characterize K ϩ channels in vas deferens from different animal species. [3][4][5][6][7] The motor innervation of the human vas deferens is mainly noradrenergic, 8,9 and the contraction is mediated by neurally released norepinephrine and stimulation of postjunctional ␣ 1 adrenoceptors. 10 In contrast, the contraction of vas deferens from rat, rabbit, and guinea pig in response to sympathetic nerve stimulation has been shown to be biphasic, ATP inducing the initial fast phase and norepinephrine the later slower phase.…”

mentioning

confidence: 99%

Modulation of Adrenergic Responses of Human Vas Deferens by K+ Channel Inhibitors

Medina

Segarra

Mauricio

et al. 2010

Urology

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OBJECTIVESThe present study was designed to evaluate the role of K ϩ channels in the adrenergic responses of human vas deferens as well as the intervention of dihydropyridine-sensitive Ca 2ϩ channels on modulation of adrenergic responses by K ϩ channel inhibitors. METHODSRing segments of the epididymal part of the vas deferens were taken from 32 elective vasectomies and mounted in organ baths for isometric recording of tension. We then studied the effects of K ϩ channel blockers on neurogenic and norepinephrine-induced contractile responses. RESULTSAddition of tetraethylammonium (TEA, 10 Ϫ3 M), a nonspecific K ϩ channel blocker, or charybdotoxin (10 Ϫ7 M), a nonselective inhibitor of large-and intermediate-conductance Ca 2ϩ -activated K ϩ channel, increased the contractile responses to norepinephrine and electrical field stimulation-induced contractions (P Ͻ .01), whereas iberiotoxin (10 Ϫ7 M), a selective blocker of large-conductance Ca 2ϩ -activated K ϩ channels, apamin (10 Ϫ6 M), a blocker of small-conductance Ca 2ϩ -activated K ϩ channels, or glibenclamide (10 Ϫ5 M), an inhibitor of ATP-sensitive K ϩ channels, were without effect. TEA-and charybdotoxin-induced potentiation of contractions elicited by electrical field stimulation and norepinephrine was blocked by L-type Ca 2ϩ channel blocker nifedipine (10 Ϫ6 M). CONCLUSIONSThe results suggest that charybdotoxin-sensitive, but iberiotoxin-insensitive, K ϩ channels are activated by stimulation with norepinephrine and electrical field stimulation to counteract the adrenergic-induced contractions of human vas deferens. Thus, inhibition of these channels increases significantly the contraction, an effect that appears to be mediated by an increase in Ca 2ϩ entry through L-type voltage-dependent Ca 2ϩ channels. UROLOGY 76: 1518.e7-1518.e12, 2010.

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Local Ca²⁺ transients and distribution of BK channels and ryanodine receptors in smooth muscle cells of guinea‐pig vas deferens and urinary bladder

Cited by 100 publications

References 43 publications

Inositol 1,4,5-trisphosphate receptors modulate Ca²⁺ sparks and Ca²⁺ store content in vas deferens myocytes

Inositol 1,4,5-trisphosphate receptors modulate Ca²⁺ sparks and Ca²⁺ store content in vas deferens myocytes

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

Modulation of Adrenergic Responses of Human Vas Deferens by K+ Channel Inhibitors

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Local Ca2+ transients and distribution of BK channels and ryanodine receptors in smooth muscle cells of guinea‐pig vas deferens and urinary bladder

Cited by 100 publications

References 43 publications

Inositol 1,4,5-trisphosphate receptors modulate Ca2+ sparks and Ca2+ store content in vas deferens myocytes

Inositol 1,4,5-trisphosphate receptors modulate Ca2+ sparks and Ca2+ store content in vas deferens myocytes

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

Modulation of Adrenergic Responses of Human Vas Deferens by K+ Channel Inhibitors

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Local Ca²⁺ transients and distribution of BK channels and ryanodine receptors in smooth muscle cells of guinea‐pig vas deferens and urinary bladder

Inositol 1,4,5-trisphosphate receptors modulate Ca²⁺ sparks and Ca²⁺ store content in vas deferens myocytes

Inositol 1,4,5-trisphosphate receptors modulate Ca²⁺ sparks and Ca²⁺ store content in vas deferens myocytes