Suppression of cAMP by phosphoinositol/Ca2+ pathway in the cardiac κ-opioid receptor

1998 ◽  
Vol 274 (1) ◽  
pp. C82-C87 ◽  
Author(s):  
Wei-Min Zhang ◽  
Tak-Ming Wong
Keyword(s):  
Receptor Agonist ◽  
Ventricular Myocytes ◽  
Tetraacetic Acid ◽  
Acetoxymethyl Ester ◽  
Receptor Stimulation ◽  
Camp Pathway ◽  
A 23187 ◽  
Intracellular Ca ◽  
First Time ◽  
Κ Receptor

To determine whether the phosphoinositol/Ca2+ pathway interacts with the adenylate cyclase/adenosine 3′,5′-cyclic monophosphate (cAMP) pathway in the cardiac κ-receptor, the effects of U-50488, a specific κ-receptor agonist, on the intracellular Ca2+ concentration ([Ca2+]i) and forskolin-induced accumulation of cAMP in rat ventricular myocytes were determined after interference of the phosphoinositol/Ca2+ pathway. U-50488 suppressed the forskolin-induced accumulation of cAMP and elevated [Ca2+]i, which were blocked by norbinaltorphimine, a specific κ-receptor antagonist, and pertussis toxin. The effects of U-50488 were qualitatively similar to those of A-23187, a Ca2+ ionophore, but opposite to those of 1,2-bis(2-aminophenoxy)ethane- N, N, N′, N′-tetraacetic acid (BAPTA)-acetoxymethyl ester (AM), a [Ca2+]ichelator. Abolition of U-50488-induced elevation of [Ca2+]iby BAPTA-AM also abolished the effect of U-50488 on forskolin-induced accumulation of cAMP. Inhibition of the phospholipase C by specific inhibitors, U-73122 and neomycin, abolished the effects of U-50488 on both [Ca2+]iand forskolin-induced accumulation of cAMP. The results showed for the first time that κ-receptor stimulation may suppress cAMP accumulation via activation of the phosphoinositol/Ca2+ pathway in the rat heart.

scholarly journals Acidosis antagonizes intracellular calcium response to κ-opioid receptor stimulation in the rat heart

1999 ◽  
Vol 277 (3) ◽  
pp. C492-C500 ◽  
Author(s):  
Jian-Ming Pei ◽  
Xiao-Chun Yu ◽  
Jin-Song Bian ◽  
Tak-Ming Wong
Keyword(s):  
Opioid Receptor ◽  
Receptor Agonist ◽  
Ventricular Myocytes ◽  
High Concentration ◽  
Receptor Stimulation ◽  
Antagonistic Action ◽  
Extracellular Acidosis ◽  
Opioid Receptor Agonist ◽  
Intracellular Ca ◽  
First Time

To study the effects of κ-opioid receptor stimulation on intracellular Ca2+ concentration ([Ca2+]i) homeostasis during extracellular acidosis, we determined the effects of κ-opioid receptor stimulation on [Ca2+]iresponses during extracellular acidosis in isolated single rat ventricular myocytes, by a spectrofluorometric method. U-50488H (10–30 μM), a selective κ-opioid receptor agonist, dose dependently decreased the electrically induced [Ca2+]itransient, which results from the influx of Ca2+ and the subsequent mobilization of Ca2+ from the sarcoplasmic reticulum (SR). U-50488H (30 μM) also increased the resting [Ca2+]iand inhibited the [Ca2+]itransient induced by caffeine, which mobilizes Ca2+ from the SR, indicating that the effects of the κ-opioid receptor agonist involved mobilization of Ca2+ from its intracellular pool into the cytoplasm. The Ca2+responses to 30 μM U-50488H were abolished by 5 μM nor-binaltorphimine, a selective κ-opioid receptor antagonist, indicating that the event was mediated by the κ-opioid receptor. The effects of the agonist on [Ca2+]iand the electrically induced [Ca2+]itransient were significantly attenuated when the extracellular pH (pHe) was lowered to 6.8, which itself reduced intracellular pH (pHi) and increased [Ca2+]i. The inhibitory effects of U-50488H were restored during extracellular acidosis in the presence of 10 μM ethylisopropyl amiloride, a potent Na+/H+exchange blocker, or 0.2 mM Ni2+, a putative Na+/Ca2+exchange blocker. The observations indicate that acidosis may antagonize the effects of κ-opioid receptor stimulation via Na+/H+and Na+/Ca2+exchanges. When glucose at 50 mM, known to activate the Na+/H+exchange, was added, both the resting [Ca2+]iand pHi increased. Interestingly, the effects of U-50488H on [Ca2+]iand the electrically induced [Ca2+]itransient during superfusion with glucose were significantly attenuated; this mimicked the responses during extracellular acidosis. When a high-Ca2+ (3 mM) solution was superfused, the resting [Ca2+]iincreased; the increase was abolished by 0.2 mM Ni2+, but the pHi remained unchanged. Like the responses to superfusion with high-concentration glucose and extracellular acidosis, the responses of the [Ca2+]iand electrically induced [Ca2+]itransients to 30 μM U-50488H were also significantly attenuated. Results from the present study demonstrated for the first time that extracellular acidosis antagonizes the effects of κ-opioid receptor stimulation on the mobilization of Ca2+ from SR. Activation of both Na+/H+and Na+/Ca2+exchanges, leading to an elevation of [Ca2+]i, may be responsible for the antagonistic action of extracellular acidosis against κ-opioid receptor stimulation.

Ets-1 is an early response gene activated by ET-1 and PDGF-BB in vascular smooth muscle cells

1998 ◽  
Vol 274 (2) ◽  
pp. C472-C480 ◽  
Author(s):  
Shinji Naito ◽  
Shunichi Shimizu ◽  
Shigeto Maeda ◽  
Jianwei Wang ◽  
Richard Paul ◽  
...  
Keyword(s):  
Gene Expression ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Inositol Phosphate ◽  
Muscle Cells ◽  
Tetraacetic Acid ◽  
Acetoxymethyl Ester ◽  
Intracellular Ca

Ets-1 is a transcription factor that activates expression of matrix-degrading proteinases such as collagenase and stromelysin. To study the control of ets-1 gene expression in rat vascular smooth muscle cells (VSMC), cells were exposed to factors known to regulate VSMC migration and proliferation. Platelet-derived growth factor-BB (PDGF-BB), endothelin-1 (ET-1), and phorbol 12-myristate 13-acetate (PMA) induced a dose-dependent expression of ets-1 mRNA. These effects were abrogated by inhibition of protein kinase C (PKC) by H-7 or chronic PMA treatment. Ets-1 mRNA was superinduced by PDGF-BB and ET-1 in the presence of cycloheximide. The chelation of intracellular Ca2+ by 1,2-bis(2-aminophenoxy)ethane- N, N, N′, N′-tetraacetic acid-acetoxymethyl ester and the depletion of endoplasmic reticulum intracellular Ca2+concentration ([Ca2+]i) by thapsigargin inhibited PDGF-BB- and ET-1-induced ets-1 mRNA, whereas ethylene glycol-bis(β-aminoethyl ether)- N, N, N′, N′-tetraacetic acid had no effect. However, [Ca2+]irelease alone was not sufficient to increase ets-1 mRNA. Forskolin blocked ET-1-, PDGF-BB-, and PMA-induced ets-1 mRNA, as well as inositol phosphate formation, consistent with an effect through impairment of PKC activation. Inhibitors of ets-1 gene expression, such as H-7 and herbimycin A, inhibited the ET-1 induction of collagenase I mRNA. We propose that ets-1 may be an important element in the orchestration of matrix proteinase expression and of vascular remodeling after arterial injury.

scholarly journals Adenosine A1receptor-mediated antiadrenergic effects are modulated by A2a receptor activation in rat heart

1999 ◽  
Vol 276 (2) ◽  
pp. H341-H349 ◽  
Author(s):  
Gavin R. Norton ◽  
Angela J. Woodiwiss ◽  
Robert J. McGinn ◽  
Mojca Lorbar ◽  
Eugene S. Chung ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Receptor Agonist ◽  
Ventricular Myocytes ◽  
Physiological Role ◽  
Receptor Activation ◽  
Dependent Manner ◽  
Receptor Antagonists ◽  
Rat Hearts ◽  
Intracellular Ca ◽  
Perfused Rat Hearts

Presently, the physiological significance of myocardial adenosine A2a receptor stimulation is unclear. In this study, the influence of adenosine A2a receptor activation on A1 receptor-mediated antiadrenergic actions was studied using constant-flow perfused rat hearts and isolated rat ventricular myocytes. In isolated perfused hearts, the selective A2a receptor antagonists 8-(3-chlorostyryl)caffeine (CSC) and 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM-241385) potentiated adenosine-mediated decreases in isoproterenol (Iso; 10−8 M)-elicited contractile responses (+dP/d t max) in a dose-dependent manner. The effect of ZM-241385 on adenosine-induced antiadrenergic actions was abolished by the selective A1 receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (10−7 M), but not the selective A3 receptor antagonist 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate (MRS-1191, 10−7 M). The A2a receptor agonist carboxyethylphenethyl-aminoethyl-carboxyamido-adenosine (CGS-21680) at 10−5 M attenuated the antiadrenergic effect of the selective A1 receptor agonist 2-chloro- N 6-cyclopentyladenosine (CCPA), whereas CSC did not influence the antiadrenergic action of this agonist. In isolated ventricular myocytes, CSC potentiated the inhibitory action of adenosine on Iso (2 × 10−7 M)-elicited increases in intracellular Ca2+concentration ([Ca2+]i) transients but did not influence Iso-induced changes in [Ca2+]itransients in the absence of exogenous adenosine. These results indicate that adenosine A2areceptor antagonists enhance A1-receptor-induced antiadrenergic responses and that A2a receptor agonists attenuate (albeit to a modest degree) the antiadrenergic actions of A1 receptor activation. In conclusion, the data in this study support the notion that an important physiological role of A2a receptors in the normal mammalian myocardium is to reduce A1 receptor-mediated antiadrenergic actions.

Isolated ventricular myocytes from copper-deficient rat hearts exhibit enhanced contractile function

2001 ◽  
Vol 281 (2) ◽  
pp. H476-H481 ◽  
Author(s):  
Loren E. Wold ◽  
Jack T. Saari ◽  
Jun Ren
Keyword(s):  
Cardiac Fibrosis ◽  
Copper Deficiency ◽  
Ventricular Myocytes ◽  
Contractile Function ◽  
Detection System ◽  
Cardiac Contractile Function ◽  
Acetoxymethyl Ester ◽  
Cardiac Contractile ◽  
Rat Hearts ◽  
Intracellular Ca

Dietary copper deficiency leads to cardiac hypertrophy, cardiac fibrosis, derangement of myofibrils, and impaired cardiac contractile and electrophysiological function. The purpose of this study was to determine whether impaired cardiac function from copper deficiency is due to depressed contractile function at the single myocyte level. Male Sprague-Dawley rats were fed diets that were either copper adequate (5.59–6.05 μg copper/g body wt; n = 11) or copper deficient (0.29–0.34 μg copper/g body wt; n = 11) for 5 wk. Ventricular myocytes were dispersed and mechanical properties were evaluated using the SoftEdge video-based edge-detection system. Intracellular Ca2+ transients were examined using fura 2-acetoxymethyl ester. Myocytes were electrically stimulated to contract at 0.5 Hz. Properties evaluated included peak shortening (PS), time to peak shortening (TPS), time to 90% relengthening (TR90), and maximal velocities of shortening and relengthening (±d L/d t). Myocytes from the copper-deficient rat hearts exhibited significantly enhanced PS values associated with shortened TR90 measurements compared with those from copper-adequate rat hearts. The ±d L/d t values were enhanced and the intracellular Ca2+ transient decay rate was depressed in myocytes from copper-deficient rats. These data indicate that impaired cardiac contractile function that is seen in copper-deficient whole hearts might not be due to depressed cardiac contractile function at the single cell level but rather to other mechanisms such as cardiac fibrosis.

Simultaneous changes in intracellular calcium and tension induced by endothelin-1 and sarafotoxin S6c in guinea pig isolated gallbladder: influence of indomethacin

2002 ◽  
Vol 80 (5) ◽  
pp. 458-463 ◽  
Author(s):  
Alcíbia M Cardozo ◽  
Pedro D'Orléans-Juste ◽  
Ghassan Bkaily ◽  
Giles A Rae
Keyword(s):  
Smooth Muscle ◽  
Guinea Pig ◽  
Intracellular Calcium ◽  
Fluorescence Intensity ◽  
Receptor Agonist ◽  
Muscle Tension ◽  
Strongly Correlated ◽  
Receptor Stimulation ◽  
Endothelin 1 ◽  
Intracellular Ca

The relationships between changes in intracellular Ca2+ and smooth muscle tension triggered by endothelin-1 and the selective endothelin ETB receptor agonist sarafotoxin S6c, as well as their susceptibility to modification by the nonselective cyclooxygenase blocker indomethacin, were assessed in guinea pig isolated gallbladder strips. Cumulative additions of either agonist (1, 10, and 100 nM) induced simultaneous graded, strongly correlated, slowly developing, and sustained changes in tension and intracellular Ca+2 (Fura-2 technique). Sarafotoxin S6c was more effective than endothelin-1 in raising intracellular Ca2+ at 1 or 10 nM, but their abilities to cause contractions were similar at all concentrations. Indomethacin (5.6 µM) markedly inhibited the changes in both intracellular Ca2+ and tension caused by all concentrations of sarafotoxin S6c (in response to 100 nM, increases in Ca+2 fluorescence intensity and tension were inhibited from 7.7 ± 0.7 to 4.0 ± 0.4% and from 460 ± 100 to 160 ± 40 mg, respectively) but only reduced the contraction triggered by 100 nM endothelin-1 (from 560 ± 100 to 230 ± 70 mg). Endothelin-1 caused greater prostacyclin release from gallbladder than sarafotoxin S6c (at 100 nM, 6-keto-PGF1α levels in the medium rose 4.8- and 2.8-fold, respectively; P < 0.05) and slightly increased thromboxane A2 release (1.6-fold; P < 0.05). Thus, gallbladder contractions triggered by combined ETA/ETB or selective ETB receptor stimulation (with endothelin-1 or sarafotoxin S6c, respectively) are strongly correlated with increases in intracellular Ca2+ but differentially affected by indomethacin. It remains to be assessed if this difference is because endothelin-1 triggers greater prostacyclin release than sarafotoxin S6c and (or) is due to the coupling of ETA and ETB receptors to distinct patterns of generation of cyclooxygenase-derived eicosanoids.Key words: endothelin, gallbladder, prostacyclin, indomethacin, calcium.

Role of Ca2+ fluctuations in L6 myotubes in the regulation of the hexokinase II gene

2000 ◽  
Vol 88 (2) ◽  
pp. 669-673 ◽  
Author(s):  
Amy E. Halseth ◽  
Robert M. O'Doherty ◽  
Richard L. Printz ◽  
Deanna P. Bracy ◽  
Daryl K. Granner ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Contraction ◽  
Moderate Intensity ◽  
Hexokinase Ii ◽  
Moderate Intensity Exercise ◽  
Acetoxymethyl Ester ◽  
L6 Myotubes ◽  
Threefold Increase ◽  
A 23187 ◽  
Intracellular Ca

Expression of the hexokinase (HK) II gene in skeletal muscle is upregulated by electrically stimulated muscle contraction and moderate-intensity exercise. However, the molecular mechanism by which this occurs is unknown. Alterations in intracellular Ca2+homeostasis accompany contraction and regulate gene expression in contracting skeletal muscle. Therefore, as a first step in understanding the exercise-induced increase in HK II, the ability of Ca2+ to increase HK II mRNA was investigated in cultured skeletal muscle cells, namely L6 myotubes. Exposure of cells to the ionophore A-23187 resulted in an approximately threefold increase in HK II mRNA. Treatment of cells with the extracellular Ca2+chelator EGTA did not alter HK II mRNA, nor was it able to prevent the A-23187-induced increase. Treatment of cells with the intracellular Ca2+ chelator 1,2-bis( o-aminophenoxy)ethane- N,N,N′,N′-tetraacetic acid tetra(acetoxymethyl) ester (BAPTA-AM) also resulted in an approximately threefold increase in HK II mRNA in the absence of ionophore, which was similar to the increase in HK II mRNA induced by the combination of BAPTA-AM and A-23187. In summary, a rise in intracellular Ca2+ is not necessary for the A-23187-induced increase in HK II mRNA, and increases in HK II mRNA occur in response to treatments that decrease intracellular Ca2+ stores. Depletion of intracellular Ca2+stores may be one mechanism by which muscle contraction increases HK II mRNA.

Ca current facilitation during postrest recovery depends on Ca entry

1990 ◽  
Vol 259 (3) ◽  
pp. H951-H961 ◽  
Author(s):  
L. V. Hryshko ◽  
D. M. Bers
Keyword(s):  
Steady State ◽  
Ventricular Myocytes ◽  
Rest Period ◽  
Tetraacetic Acid ◽  
Ca Current ◽  
Step Potential ◽  
Recovery From Inactivation ◽  
Intracellular Ca ◽  
Steady State Levels ◽  
Current Facilitation

Whole cell Ca current (ICa) recovery after periods of rest was examined in voltage-clamped rabbit ventricular myocytes with Na and K currents suppressed. To evaluate rest-dependent changes in ICa independent of the effects of sarcoplasmic reticular (SR) Ca release, the intracellular Ca ([Ca]i) transients were usually buffered by ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (10 mM) in the patch pipette. When voltage-clamp pulses were resumed (at 0.5 Hz) after a period of rest, several pulses were required to reattain steady-state peak ICa levels. From depolarized holding potentials between -40 and -50 mV, peak ICa of the first pulse was large and gradually decayed to steady-state levels (negative ICa staircase). This potentiation of postrest ICa was mediated by increased recovery from inactivation of Ca channels during the rest period. In contrast, with more negative holding potentials (-70 to -90 mV), the initial postrest ICa was relatively small (rest depression) and facilitation of ICa was then observed for subsequent pulses (positive ICa staircase). This ICa facilitation was mediated by a progressive decrease in the ICa inactivation rate. Depression of the initial postrest ICa required 10-15 s of rest to fully develop and became relatively constant for longer rest intervals (30-300 s). Postrest ICa depression (i.e., subsequent ICa facilitation) was abolished by replacement of extracellular Ca ([Ca]o) with either Ba or Sr. Thus ICa facilitation depends on Ca entry. Increasing [Ca]o increased postrest ICa facilitation and reducing [Ca]o had an opposite effect. When ICa was altered by changing step potential, maximal ICa facilitation occurred when ICa was maximal. Thus ICa facilitation can be graded by the amount of Ca entry. As ICa facilitation was not altered by ryanodine, this response is not likely to be due to SR Ca release. However, increasing [Ca]i buffering by using 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid in the pipette abolished the ICa staircase. Our results indicate that Ca entry can facilitate subsequent ICa, presumably through actions occurring near the sarcolemma. These local changes in [Ca]i lead to a progressive slowing in the rate of ICa inactivation.

Impaired [Ca2+]i and pHiresponses to κ-opioid receptor stimulation in the heart of chronically hypoxic rats

2000 ◽  
Vol 279 (5) ◽  
pp. C1483-C1494 ◽  
Author(s):  
Jian-Ming Pei ◽  
Jing-Jun Zhou ◽  
Jin-Song Bian ◽  
Xiao-Chun Yu ◽  
Man-Lung Fung ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Ventricular Myocytes ◽  
Specific Inhibitor ◽  
Receptor Stimulation ◽  
Calphostin C ◽  
Kinase C ◽  
Intracellular Ca ◽  
Regional Specificity ◽  
Single Ventricular Myocytes ◽  
Pkc Activation

κ-Opioid receptor (κ-OR) stimulation with U50,488H, a selective κ-OR agonist, or activation of protein kinase C (PKC) with 4-phorbol 12-myristate 13-acetate (PMA), an activator of PKC, decreased the electrically induced intracellular Ca2+ ([Ca2+]i) transient and increased the intracellular pH (pHi) in single ventricular myocytes of rats subjected to 10% oxygen for 4 wk. The effects of U50,488H were abolished by nor-binaltorphimine, a selective κ-OR antagonist, and calphostin C, a specific inhibitor of PKC, while the effects of PMA were abolished by calphostin C and ethylisopropylamiloride (EIPA), a potent Na+/H+exchange blocker. In both right hypertrophied and left nonhypertrophied ventricles of chronically hypoxic rats, the effects of U50,488H or PMA on [Ca2+]i transient and pHi were significantly attenuated and completely abolished, respectively. Results are first evidence that the [Ca2+]i and pHi responses to κ-OR stimulation are attenuated in the chronically hypoxic rat heart, which may be due to reduced responses to PKC activation. Responses to all treatments were the same for right and left ventricles, indicating that the functional impairment is independent of hypertrophy. κ-OR mRNA expression was the same in right and left ventricles of both normoxic and hypoxic rats, indicating no regional specificity.

Carbachol promotes Na+ entry and augments Na/Ca exchange current in guinea pig ventricular myocytes

1997 ◽  
Vol 273 (4) ◽  
pp. H1984-H1993
Author(s):  
Tomoaki Saeki ◽  
Jian-Bing Shen ◽  
Achilles J. Pappano
Keyword(s):  
Steady State ◽  
Guinea Pig ◽  
Ventricular Myocytes ◽  
Outward Current ◽  
Exchange Current ◽  
Tetraacetic Acid ◽  
Induced Current ◽  
Tyrode Solution ◽  
Intracellular Ca ◽  
Induced Charge

The effect of carbachol (CCh) on the Na/Ca exchange current ( I Na/Ca) was studied in voltage-clamped ventricular myocytes isolated from guinea pig hearts and superfused with Tyrode solution at 35°C. CCh (100 μM) increased outward current during depolarizations (10–200 ms) from −45 mV and tail current amplitude on repolarization; CCh had no effect on the L-type Ca2+current. Amplitudes of the outward and tail currents declined with increasing duration of the depolarizing clamp pulse. Ouabain produced similar current changes that are suppressed by intrapipette ethylene glycol-bis(β-aminoethyl ether)- N, N, N′, N′-tetraacetic acid and are characteristic of I Na/Ca. Depolarization from −80 to −30 mV elicited the rapid Na+ current followed by a slowly decaying inward I Na/Ca (J. C. Gilbert, T. Shirayama, and A. J. Pappano. Circ. Res. 69: 1632–1639, 1991.) that was reversibly increased by CCh. Atropine (1–3 μM) prevented the CCh effect. All procedures that suppressed I Na/Caalso suppressed the CCh effect. Sarcoplasmic reticulum (SR) Ca2+ release participated in generating I Na/Cabecause 10 mM caffeine or 1 μM ryanodine blocked I Na/Ca and the effect of CCh. Rapid superfusion of 10 mM caffeine induced inward I Na/Ca at −75 mV; a caffeine-induced charge transfer gives an SR Ca2+ content of 67 μM. CCh increased caffeine-induced current; SR Ca2+ content rose to 98 μM. CCh also augmented the amplitude of steady-state intracellular Ca2+ transients and contractions during a train of voltage-clamp pulses (−75 to 30 mV for 200 ms) at 1 Hz. CCh elevated intracellular Na+ (M. Korth and V. Kühlkamp. Pflügers Arch.403: 266–272, 1985) by inducing a background Na+ current [K. Matsumoto and A. J. Pappano. J. Physiol. (Lond.)415: 487–502, 1989]. Together with these data, the present results are consistent with the hypothesis that CCh, via muscarinic receptors, eventually promotes I Na/Ca at the sarcolemma through a mechanism that requires the SR and that this action accounts for the increased contractions.

scholarly journals Cardiac small-conductance calcium-activated potassium channels in health and disease

2021 ◽  
Vol 473 (3) ◽  
pp. 477-489 ◽  
Author(s):  
Xiao-Dong Zhang ◽  
Phung N. Thai ◽  
Deborah K. Lieu ◽  
Nipavan Chiamvimonvat
Keyword(s):  
Ventricular Myocytes ◽  
Pulmonary Veins ◽  
Differential Sensitivity ◽  
Sk Channels ◽  
Sk Channel ◽  
Ventricular Cells ◽  
Intracellular Ca ◽  
Life Threatening ◽  
Health And Disease ◽  
Small Conductance

AbstractSmall-conductance Ca2+-activated K+ (SK, KCa2) channels are encoded by KCNN genes, including KCNN1, 2, and 3. The channels play critical roles in the regulation of cardiac excitability and are gated solely by beat-to-beat changes in intracellular Ca2+. The family of SK channels consists of three members with differential sensitivity to apamin. All three isoforms are expressed in human hearts. Studies over the past two decades have provided evidence to substantiate the pivotal roles of SK channels, not only in healthy heart but also with diseases including atrial fibrillation (AF), ventricular arrhythmia, and heart failure (HF). SK channels are prominently expressed in atrial myocytes and pacemaking cells, compared to ventricular cells. However, the channels are significantly upregulated in ventricular myocytes in HF and pulmonary veins in AF models. Interests in cardiac SK channels are further fueled by recent studies suggesting the possible roles of SK channels in human AF. Therefore, SK channel may represent a novel therapeutic target for atrial arrhythmias. Furthermore, SK channel function is significantly altered by human calmodulin (CaM) mutations, linked to life-threatening arrhythmia syndromes. The current review will summarize recent progress in our understanding of cardiac SK channels and the roles of SK channels in the heart in health and disease.

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