scholarly journals Interplay among distinct Ca2+conductances drives Ca2+sparks/spontaneous transient outward currents in rat cerebral arteries

2016 ◽  
Vol 595 (4) ◽  
pp. 1111-1126 ◽  
Author(s):  
Ahmed M. Hashad ◽  
Neil Mazumdar ◽  
Monica Romero ◽  
Anders Nygren ◽  
Kamran Bigdely-Shamloo ◽  
...  
Keyword(s):  
Cerebral Arteries ◽  
Outward Currents ◽  
Spontaneous Transient Outward Currents

Frequency modulation of Ca2+sparks is involved in regulation of arterial diameter by cyclic nucleotides

1998 ◽  
Vol 274 (5) ◽  
pp. C1346-C1355 ◽  
Author(s):  
Valerie A. Porter ◽  
Adrian D. Bonev ◽  
Harm J. Knot ◽  
Thomas J. Heppner ◽  
Andra S. Stevenson ◽  
...  
Keyword(s):  
Arterial Wall ◽  
Cerebral Arteries ◽  
Mean Amplitude ◽  
Arterial Diameter ◽  
Outward Currents ◽  
Voltage Dependent ◽  
The Mean ◽  
Camp Levels ◽  
Spontaneous Transient Outward Currents ◽  
External K

Forskolin, which elevates cAMP levels, and sodium nitroprusside (SNP) and nicorandil, which elevate cGMP levels, increased, by two- to threefold, the frequency of subcellular Ca2+ release (“Ca2+ sparks”) through ryanodine-sensitive Ca2+ release (RyR) channels in the sarcoplasmic reticulum (SR) of myocytes isolated from cerebral and coronary arteries of rats. Forskolin, SNP, nicorandil, dibutyryl-cAMP, and adenosine increased the frequency of Ca2+-sensitive K+(KCa) currents [“spontaneous transient outward currents” (STOCs)] by two- to threefold, consistent with Ca2+ sparks activating STOCs. These agents also increased the mean amplitude of STOCs by 1.3-fold, an effect that could be explained by activation of KCa channels, independent of effects on Ca2+ sparks. To test the hypothesis that cAMP could act to dilate arteries through activation of the Ca2+spark→KCa channel pathway, the effects of blockers of KCachannels (iberiotoxin) and of Ca2+sparks (ryanodine) on forskolin-induced dilations of pressurized cerebral arteries were examined. Forskolin-induced dilations were partially inhibited by iberiotoxin and ryanodine (with no additive effects) and were entirely prevented by elevating external K+. Forskolin lowered average Ca2+ in pressurized arteries while increasing ryanodine-sensitive, caffeine-induced Ca2+ transients. These experiments suggest a new mechanism for cyclic nucleotide-mediated dilations through an increase in Ca2+ spark frequency, caused by effects on SR Ca2+ load and possibly on the RyR channel, which leads to increased STOC frequency, membrane potential hyperpolarization, closure of voltage-dependent Ca2+ channels, decrease in arterial wall Ca2+, and, ultimately, vasodilation.

scholarly journals Intracellular calcium events activated by ATP in murine colonic myocytes

2000 ◽  
Vol 279 (1) ◽  
pp. C126-C135 ◽  
Author(s):  
Orline Bayguinov ◽  
Brian Hagen ◽  
Adrian D. Bonev ◽  
Mark T. Nelson ◽  
Kenton M. Sanders
Keyword(s):  
Ryanodine Receptors ◽  
Smooth Muscles ◽  
Sk Channels ◽  
Inhibitory Neurotransmitter ◽  
Outward Currents ◽  
Ionic Conductances ◽  
Visceral Muscles ◽  
Murine Colon ◽  
Spontaneous Transient Outward Currents ◽  
Purinergic Stimulation

ATP is a candidate enteric inhibitory neurotransmitter in visceral smooth muscles. ATP hyperpolarizes visceral muscles via activation of small-conductance, Ca2+-activated K+ (SK) channels. Coupling between ATP stimulation and SK channels may be mediated by localized Ca2+ release. Isolated myocytes of the murine colon produced spontaneous, localized Ca2+ release events. These events corresponded to spontaneous transient outward currents (STOCs) consisting of charybdotoxin (ChTX)-sensitive and -insensitive events. ChTX-insensitive STOCs were inhibited by apamin. Localized Ca2+ transients were not blocked by ryanodine, but these events were reduced in magnitude and frequency by xestospongin C (Xe-C), a blocker of inositol 1,4,5-trisphosphate receptors. Thus we have termed the localized Ca2+ events in colonic myocytes “Ca2+ puffs.” The P2Y receptor agonist 2-methylthio-ATP (2-MeS-ATP) increased the intensity and frequency of Ca2+ puffs. 2-MeS-ATP also increased STOCs in association with the increase in Ca2+ puffs. Pyridoxal-phospate-6-azophenyl-2′,4′-disculfonic acid tetrasodium, a P2 receptor inhibitor, blocked responses to 2-MeS-ATP. Spontaneous Ca2+ transients and the effects of 2-MeS-ATP on Ca2+ puffs and STOCs were blocked by U-73122, an inhibitor of phospholipase C. Xe-C and ryanodine also blocked responses to 2-MeS-ATP, suggesting that, in addition to release from IP3receptor-operated stores, ryanodine receptors may be recruited during agonist stimulation to amplify release of Ca2+. These data suggest that localized Ca2+ release modulates Ca2+-dependent ionic conductances in the plasma membrane. Localized Ca2+ release may contribute to the electrical responses resulting from purinergic stimulation.

Spontaneous transient outward currents and delayed rectifier K+ current: effects of hypoxia

1998 ◽  
Vol 275 (1) ◽  
pp. L145-L154 ◽  
Author(s):  
C. Vandier ◽  
M. Delpech ◽  
P. Bonnet
Keyword(s):  
Steady State ◽  
Outward Current ◽  
Delayed Rectifier ◽  
Patch Clamp Technique ◽  
Outward Currents ◽  
K Current ◽  
The Mean ◽  
Patch Configuration ◽  
Spontaneous Transient Outward Currents ◽  
Dependent Mechanism

Single smooth muscle cells of rabbit intrapulmonary artery were voltage clamped using the perforated-patch configuration of the patch-clamp technique. We observed spontaneous transient outward currents (STOCs) and a steady-state outward current. Because STOCs were tetraethylammonium sensitive and activated by Ca2+ influx, they were believed to represent activation of Ca2+-activated K+ channels. The steady-state outward current, which was sensitive to 4-aminopyridine, was the delayed rectifier K+ current. In cells voltage clamped at 0 mV, we found that STOCs were not randomly distributed in amplitude but were composed of multiples of 1.57 ± 0.56 pA/pF. The mean frequency of STOCs was 5.51 ± 3.49 Hz. Ryanodine (10 μM), caffeine (5 mM), thapsigargin (200 nM), and hypoxia [Formula: see text] = 10 mmHg) decreased STOCs. The effect of hypoxia on STOCs was partially reversible only if the experiment was conducted in the presence of thapsigargin. Hypoxia and thapsigargin decrease steady-state outward current. Thapsigargin and removal of external Ca2+abolished the effect of hypoxia, suggesting that hypoxia decreases steady-state outward current by a Ca2+-dependent mechanism.

Spontaneous transient outward currents in smooth muscle cells

Cell Calcium ◽  
1996 ◽  
Vol 20 (2) ◽  
pp. 141-152 ◽  
Author(s):  
T.B. Bolton ◽  
Y. Imaizumi
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Outward Currents ◽  
Spontaneous Transient Outward Currents

scholarly journals The Influence of Sarcoplasmic Reticulum Ca2+ Concentration on Ca2+ Sparks and Spontaneous Transient Outward Currents in Single Smooth Muscle Cells

1999 ◽  
Vol 113 (2) ◽  
pp. 215-228 ◽  
Author(s):  
Ronghua ZhuGe ◽  
Richard A. Tuft ◽  
Kevin E. Fogarty ◽  
Karl Bellve ◽  
Fredric S. Fay ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Sarcoplasmic Reticulum ◽  
Potassium Channels ◽  
Smooth Muscle Cells ◽  
High Speed ◽  
Muscle Cells ◽  
Wide Field ◽  
Outward Currents ◽  
The Relationship ◽  
Spontaneous Transient Outward Currents

Localized, transient elevations in cytosolic Ca2+, known as Ca2+ sparks, caused by Ca2+ release from sarcoplasmic reticulum, are thought to trigger the opening of large conductance Ca2+-activated potassium channels in the plasma membrane resulting in spontaneous transient outward currents (STOCs) in smooth muscle cells. But the precise relationships between Ca2+ concentration within the sarcoplasmic reticulum and a Ca2+ spark and that between a Ca2+ spark and a STOC are not well defined or fully understood. To address these problems, we have employed two approaches using single patch-clamped smooth muscle cells freshly dissociated from toad stomach: a high speed, wide-field imaging system to simultaneously record Ca2+ sparks and STOCs, and a method to simultaneously measure free global Ca2+ concentration in the sarcoplasmic reticulum ([Ca2+]SR) and in the cytosol ([Ca2+]CYTO) along with STOCs. At a holding potential of 0 mV, cells displayed Ca2+ sparks and STOCs. Ca2+ sparks were associated with STOCs; the onset of the sparks coincided with the upstroke of STOCs, and both had approximately the same decay time. The mean increase in [Ca2+]CYTO at the time and location of the spark peak was ∼100 nM above a resting concentration of ∼100 nM. The frequency and amplitude of spontaneous Ca2+ sparks recorded at −80 mV were unchanged for a period of 10 min after removal of extracellular Ca2+ (nominally Ca2+-free solution with 50 μM EGTA), indicating that Ca2+ influx is not necessary for Ca2+sparks. A brief pulse of caffeine (20 mM) elicited a rapid decrease in [Ca2+]SR in association with a surge in [Ca2+]CYTO and a fusion of STOCs, followed by a fast restoration of [Ca2+]CYTO and a gradual recovery of [Ca2+]SR and STOCs. The return of global [Ca2+]CYTO to rest was an order of magnitude faster than the refilling of the sarcoplasmic reticulum with Ca2+. After the global [Ca2+]CYTO was fully restored, recovery of STOC frequency and amplitude were correlated with the level of [Ca2+]SR, even though the time for refilling varied greatly. STOC frequency did not recover substantially until the [Ca2+]SR was restored to 60% or more of resting levels. At [Ca2+]SR levels above 80% of rest, there was a steep relationship between [Ca2+]SR and STOC frequency. In contrast, the relationship between [Ca2+]SR and STOC amplitude was linear. The relationship between [Ca2+]SR and the frequency and amplitude was the same for Ca2+ sparks as it was for STOCs. The results of this study suggest that the regulation of [Ca2+]SR might provide one mechanism whereby agents could govern Ca2+ sparks and STOCs. The relationship between Ca2+ sparks and STOCs also implies a close association between a sarcoplasmic reticulum Ca2+ release site and the Ca2+-activated potassium channels responsible for a STOC.

scholarly journals MicroRNA-210 Mediates Hypoxia-Induced Repression of Spontaneous Transient Outward Currents in Sheep Uterine Arteries During Gestation

Hypertension ◽  
2021 ◽  
Vol 77 (4) ◽  
pp. 1412-1427
Author(s):  
Xiang-Qun Hu ◽  
Chiranjib Dasgupta ◽  
Rui Song ◽  
Monica Romero ◽  
Sean M. Wilson ◽  
...  
Keyword(s):  
High Altitude ◽  
Intrauterine Growth Restriction ◽  
Hormonal Regulation ◽  
Outward Current ◽  
Transient Outward Current ◽  
Uterine Arteries ◽  
Outward Currents ◽  
Low Altitude ◽  
Spontaneous Transient Outward Currents

Hypoxia during pregnancy is a major contributor to the pathogenesis of preeclampsia and intrauterine growth restriction. Our recent studies revealed that pregnancy-induced uterine vascular adaptation depended on the enhanced Ca 2+ spark/spontaneous transient outward current (STOC) coupling and hypoxia during gestation diminished this adaption. In the present study, we test the hypothesis of a mechanistic link of microRNA-210 (miR-210) in hypoxia-impaired Ca 2+ spark/STOC coupling in uterine arteries. Pregnant ewes acclimatized to high-altitude (3801 m) hypoxia for ≈110 days significantly increased circulation levels of miR-210 in both the ewe and her fetus. Treatment of uterine arteries from high-altitude animals with the antagomir miR-210-LNA recovered hypoxia-repressed STOCs in pregnant ewes and restored the hormonal regulation of STOCs in nonpregnant animals. In uterine arteries from low-altitude control animals, miR-210 mimic suppressed STOCs in pregnant ewes and inhibited the hormonal regulation of STOCs in nonpregnant animals. Mechanistically, miR-210 directly targeted and downregulated type 2 ryanodine receptor and large-conductance Ca 2+ -activated K + channel β1 subunit, resulting in significant decreases in Ca 2+ sparks and STOCs in uterine arteries. In addition, miR-210 indirectly decreased STOCs by targeting ten-eleven translocation methylcytosine dioxygenase. Together, the present study revealed a mechanistic link of miR-210 in hypoxia-induced repression of Ca 2+ spark/STOC coupling in uterine arteries during gestation, providing novel insights into the understanding of pregnancy complications associated with hypoxia and the potential therapeutic targets.

Oxygen-induced fetal pulmonary vasodilation is mediated by intracellular calcium activation of KCa channels

2001 ◽  
Vol 281 (6) ◽  
pp. L1379-L1385 ◽  
Author(s):  
Valerie A. Porter ◽  
Michael T. Rhodes ◽  
Helen L. Reeve ◽  
David N. Cornfield
Keyword(s):  
Smooth Muscle ◽  
Pulmonary Artery ◽  
Smooth Muscle Cells ◽  
Intracellular Calcium ◽  
Muscle Cells ◽  
Pulmonary Vasodilation ◽  
Outward Currents ◽  
Acute Increase ◽  
Pulmonary Artery Smooth Muscle ◽  
Spontaneous Transient Outward Currents

O2 sensing in fetal pulmonary artery smooth muscle is critically important in the successful transition to air breathing at birth. However, the mechanism by which the fetal pulmonary vasculature senses and responds to an acute increase in O2tension is not known. Isolated fetal pulmonary artery smooth muscle cells were kept in primary culture for 5–14 days in a hypoxic environment (20–30 mmHg). These cells showed a 25.1 ± 1.7% decrease in intracellular calcium in response to an acute increase in O2 tension. Low concentrations of caffeine (0.5 mM) and diltiazem also decreased intracellular calcium. The decrease in intracellular calcium concentration in response to increasing O2 was inhibited by iberiotoxin and ryanodine. Freshly isolated fetal pulmonary artery smooth muscle cells exhibited “spontaneous transient outward currents,” indicative of intracellular calcium spark activation of calcium-sensitive potassium channels. The frequency of spontaneous transient outward currents increased when O2 tension was increased to normoxic levels. Increasing fetal pulmonary O2 tension in acutely instrumented fetal sheep increased fetal pulmonary blood flow. Ryanodine attenuated O2-induced pulmonary vasodilation. This study demonstrates that fetal pulmonary vascular smooth muscle cells are capable of responding to an acute increase in O2tension and that this O2 response is mediated by intracellular calcium activation of calcium-sensitive potassium channels.

scholarly journals Role of IP3 in modulation of spontaneous activity in pacemaker cells of rabbit urethra

2001 ◽  
Vol 280 (5) ◽  
pp. C1349-C1356 ◽  
Author(s):  
G. P. Sergeant ◽  
M. A. Hollywood ◽  
K. D. McCloskey ◽  
N. G. McHale ◽  
K. D. Thornbury
Keyword(s):  
Cyclopiazonic Acid ◽  
Pacemaker Activity ◽  
Pacemaker Cells ◽  
Outward Currents ◽  
Inositol 1,4,5 Trisphosphate ◽  
Inward Currents ◽  
Rabbit Urethra ◽  
Patch Technique ◽  
Spontaneous Transient Outward Currents

Isolated interstitial (“pacemaker”) cells from rabbit urethra were examined using the perforated-patch technique. Under voltage clamp at −60 mV, these cells fired large spontaneous transient inward currents (STICs), averaging −860 pA and >1 s in duration, which could account for urethral pacemaker activity. Spontaneous transient outward currents (STOCs) were also observed and fell into two categories, “fast” (<100 ms in duration) and “slow” (>1 s in duration). The latter were coupled to STICs, suggesting that they shared the same mechanism, while the former occurred independently at faster rates. All of these currents were abolished by cyclopiazonic acid, caffeine, or ryanodine, suggesting that they were activated by Ca2+ release. Whend- myo-inositol 1,4,5-trisphosphate (IP3)-sensitive stores were blocked with 2-aminoethoxydiphenyl borate, the STICs and slow STOCs were abolished, but the fast STOCs remained. In contrast, the fast STOCs were more nifedipine sensitive than the STICs or the slow STOCs. These results suggest that while fast STOCs are mediated by a mechanism similar to STOCs in smooth muscle, STICs and slow STOCs are driven by IP3. These results support the hypothesis that pacemaker activity in the urethra is driven by the IP3-sensitive store.

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

2003 ◽  
Vol 285 (1) ◽  
pp. C195-C204 ◽  
Author(s):  
Carl White ◽  
J. Graham McGeown
Keyword(s):  
Smooth Muscle ◽  
Sarcoplasmic Reticulum ◽  
Guinea Pig ◽  
Vas Deferens ◽  
Confocal Imaging ◽  
Time Duration ◽  
Outward Currents ◽  
Inositol 1,4,5 Trisphosphate ◽  
Dependent Pathway ◽  
Spontaneous Transient Outward Currents

Spontaneous Ca2+ sparks were observed in fluo 4-loaded myocytes from guinea pig vas deferens with line-scan confocal imaging. They were abolished by ryanodine (100 μM), but the inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) blockers 2-aminoethoxydiphenyl borate (2-APB; 100 μM) and intracellular heparin (5 mg/ml) increased spark frequency, rise time, duration, and spread. Very prolonged Ca2+ release events were also observed in ∼20% of cells treated with IP3R blockers but not under control conditions. 2-APB and heparin abolished norepinephrine (10 μM; 0 Ca2+)-evoked Ca2+ transients but increased caffeine (10 mM; 0 Ca2+) transients in fura 2-loaded myocytes. Transients evoked by ionomycin (25 μM; 0 Ca2+) were also enhanced by 2-APB. Ca2+ sparks and transients evoked by norepinephrine and caffeine were abolished by thimerosal (100 μM), which sensitizes the IP3R to IP3. In cells voltage clamped at –40 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 Ca2+ store content in smooth muscle is limited by tonic release of Ca2+ via an IP3-dependent pathway. Blockade of IP3Rs elevates sarcoplasmic reticulum store content, promoting Ca2+ sparks and STOC activity.

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