Regulation of cardiac excitation–contraction coupling by action potential repolarization: role of the transient outward potassium current (<i>I</i><sub>to</sub>)

Sah, Rajan; Ramírez, Rafael J.; Oudit, Gavin Y.; Gidrewicz, Dominica; Trivieri, Maria G.; Zobel, Carsten; Backx, Peter H.

doi:10.1113/jphysiol.2002.026468

Cited by 236 publications

(225 citation statements)

References 127 publications

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“…potentially interesting subject for future investigation. There is evidence that I to may contribute to electromechanical coupling, and that its dysfunction may cause contractile abnormalities, 19 so the early I to changes we observed may in fact have contributed to the development of cardiomyopathy. Interestingly, there were virtually no transcriptional changes in ion channel subunit expression at 5 weeks, in contrast to the marked changes at 10 weeks.…”

Section: Are There Specific Electrophysiological Features Of the Arrhmentioning

confidence: 70%

Loss of Cardiomyocyte Integrin-Linked Kinase Produces an Arrhythmogenic Cardiomyopathy in Mice

Quang

Maguy

et al. 2015

Circ: Arrhythmia and Electrophysiology

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Background— Integrin-linked kinase (ILK), a serine/threonine protein kinase, has roles in cell signaling and molecular scaffolding. ILK mutation/deletion causes cardiomyopathic phenotypes, but the functional and electrophysiological features have not been characterized. This study investigated the structural, functional, ion channel, and electrophysiological changes associated with cardiomyocyte-directed ILK deletion in mice. Methods and Results— Adult mice with cardiomyocyte-directed ILK knockout were compared with littermate controls. Knockout mice showed markedly increased mortality, with sudden death beginning after 5 weeks and 100% mortality at 18 weeks. In 10-week-old knockout mice, spontaneous and inducible ventricular tachyarrhythmias were common, occurring in 60% and 86%, respectively, and absent in controls ( P <0.001, P <0.05 versus knockout mice). Ventricular refractoriness was prolonged, along with both QRS and QT interval. Action potentials were prolonged and displayed triggered activity. A wide range of ion currents were downregulated, including total, fast and slow components of transient outward K + current and inward rectifier K + current, along with corresponding ion channel subunit genes, providing a plausible explanation of action potential prolongation. At 5 weeks, only voltage-dependent K + currents were reduced, possibly related to direct ILK-Kv4.2 subunit interactions. Action potentials were prolonged, but no arrhythmias or cardiac dysfunction were noted. Structural remodeling was prominent at 10 weeks: connexin-43 was downregulated and redistributed to lateral cell margins, and left ventricular fibrosis occurred, with a strong regional distribution (predominating in the basal left ventricle). Conduction was slowed. High-throughput quantitative polymerase reaction gene-expression studies in 10-week-old ILK knockout showed upregulation of structural, remodeling and fibrosis-related genes, and downregulation of a wide range of ion channel and transporter subunits. Conclusions— Cardiomyocyte ILK deletion produces a lethal arrhythmogenic cardiomyopathy associated with important ion channel and structural remodeling.

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Section: Are There Specific Electrophysiological Features Of the Arrhmentioning

confidence: 70%

Loss of Cardiomyocyte Integrin-Linked Kinase Produces an Arrhythmogenic Cardiomyopathy in Mice

Quang

Maguy

et al. 2015

Circ: Arrhythmia and Electrophysiology

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“…Enhanced SR Ca 2ϩ uptake in Bin-Off mice suggests increased SR Ca 2ϩ loads. Indeed, after caffeine application, the peak I NCX (where NCX is Na ϩ ͞Ca 2ϩ exchanger) and the time integral of I NCX , which reflects the total amount of Ca 2ϩ present in the SR (20), were elevated in Bin-Off myocyte ( Fig. 3 A and B).…”

Section: Effects Of D2 Expression On Cardiac Function and Ca 2؉ Cyclingmentioning

confidence: 96%

“…3D), or K ϩ currents (Fig. 3E), each of which can affect independently Ca 2ϩ transients and myocyte contractility (20).…”

Section: Effects Of D2 Expression On Cardiac Function and Ca 2؉ Cyclingmentioning

confidence: 99%

Cardiac-specific elevations in thyroid hormone enhance contractility and prevent pressure overload-induced cardiac dysfunction

Trivieri

Oudit

Sah

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Thyroid hormone (TH) is critical for cardiac development and heart function. In heart disease, TH metabolism is abnormal, and many biochemical and functional alterations mirror hypothyroidism. Although TH therapy has been advocated for treating heart disease, a clear benefit of TH has yet to be established, possibly because of peripheral actions of TH. To assess the potential efficacy of TH in treating heart disease, type 2 deiodinase (D2), which converts the prohormone thyroxine to active triiodothyronine (T3), was expressed transiently in mouse hearts by using the tetracycline transactivator system. Increased cardiac D2 activity led to elevated cardiac T3 levels and to enhanced myocardial contractility, accompanied by increased Ca 2؉ transients and sarcoplasmic reticulum (SR) Ca 2؉ uptake. These phenotypic changes were associated with up-regulation of sarco(endo)plasmic reticulum calcium ATPase (SERCA) 2a expression as well as decreased Na ؉ ͞Ca 2؉ exchanger, ␤-myosin heavy chain, and sarcolipin (SLN) expression. In pressure overload, targeted increases in D2 activity could not block hypertrophy but could completely prevent impaired contractility and SR Ca 2؉ cycling as well as altered expression patterns of SERCA2a, SLN, and other markers of pathological hypertrophy. Our results establish that elevated D2 activity in the heart increases T3 levels and enhances cardiac contractile function while preventing deterioration of cardiac function and altered gene expression after pressure overload.calcium ͉ cardiac hypertrophy ͉ sarcoplasmic reticulum ͉ deiodinase ͉ transgenic mice T hyroid hormone (TH) is essential for normal development in vertebrates (1), with TH levels rising postnatally and peaking in the third week of life (2). This surge is critical for fetal-to-adult switch in the cardiac gene program and is responsible for changes in Ca 2ϩ homeostasis, myosin isozyme content [␣-myosin heavy chain (MHC)-to-␤-MHC switch], and action potential profile (3, 4). Intriguingly, the genetic and functional changes associated with heart failure, such as reduced Ca 2ϩ transients and ␣-MHC-to-␤-MHC shifts, which recapitulate the fetal gene program, are also observed in hypothyroidism (5, 6). In addition, TH metabolism and signaling are abnormal in heart failure (5, 7, 8). For example, circulating and cardiac triiodothyronine (T3) levels (i.e., active TH) are reduced in advanced heart disease, after acute myocardial infarction, and in patients with cardiopulmonary bypass. These T3 changes occur in association with decreased peripheral conversion of thyroxine (T4) into T3 (5, 8) and elevated cardiac deiodinase type 3 (D3) activity (9). TH receptor expression is also altered in pathological hypertrophy (10), and myocardial contractility is impaired in mice lacking TH receptors (11). Not surprisingly, TH and its analogue 3,5-diiodothyropropionic acid (DITPA) have been advocated for treating heart failure (12, 13) and for reversing cardiac dysfunction in patients with hypothyroidism (5), although TH use has been limited by car...

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“…I A has also been demonstrated to limit the back propagation of action potentials into the dendritic arbor (14), to impact long term potentiation in CA1 hippocampal neurons (15), to affect neuronal excitability in the visual cortex (16), and to modulate compartmentalization of membrane excitability in distal dendritic spines (17). Fast transient K ϩ currents in cardiac muscles contribute both to myocyte excitability (18) and to the fast repolarization phase of the cardiac action potential (2,8,19,20). Finally, the pharmacological block of channels that carry fast transient currents in gastrointestinal smooth muscle in mice supports the conclusion that the window currents carried by these channels contribute to the resting membrane potential and cellular excitability of smooth muscle (21,22).…”

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confidence: 99%

Mutant Analysis of the Shal (Kv4) Voltage-gated Fast Transient K+ Channel in Caenorhabditis elegans

Fawcett

Santi

Butler

et al. 2006

Journal of Biological Chemistry

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. We show that Shal channels also play a role as the predominant transient outward current in Caenorhabditis elegans muscle. Green fluorescent protein promoter experiments also revealed SHL-1 expression in a subset of neurons as well as in C. elegans body wall muscle and in male-specific diagonal muscles. The shl-1 (ok1168) null mutant removed all fast transient outward current from muscle cells. SHL-1 currents strongly resembled Shal currents in other species except that they were active in a more depolarized voltage range. We also determined that the remaining delayed-rectifier current in cultured myocytes was carried by the Shaker ortholog SHK-1. In shl-1 (ok1168) mutants there was a significant compensatory increase in the SHK-1 current. Male shl-1 (ok1168) animals exhibited reduced mating efficiency resulting from an apparent difficulty in locating the hermaphrodite vulva. SHL-1 channels are apparently important in fine-tuning complex behaviors, such as mating, that play a crucial role in the survival and propagation of the species.2 channels are key regulators of membrane excitability. Based on their inactivation kinetics, Kv currents can loosely be divided into two categories as follows: noninactivating or slowly inactivating K ϩ currents, and rapidly inactivating transient currents also known as "A-type" currents. A-type currents were first described in molluscan neurons by Hagiwara et al. (3) and later by Connor and Stevens (4), Neher (5), and Thompson (6). Classical A-type currents (I A ) are voltage-dependent, Ca 2ϩ -independent K ϩ currents that undergo rapid activation and inactivation. The classical A-type currents activate at subthreshold voltages and recover from inactivation quickly compared with other Kv currents. They are also characterized by strong steady-state voltagedependent inactivation. Repolarization to potentials negative to Ϫ50 mV is typically required to restore channel availability. A-type currents have a widespread distribution and are abundantly expressed in neurons and cardiac and smooth muscle cells, where they are thought to play many important physiological roles (2, 7-11).Connor and Stevens (12) proposed that the I A may determine the interspike interval in repetitively firing neurons. Studies in cerebellar granule cells demonstrated a role for I A in determining the latency to first spike (13). I A has also been demonstrated to limit the back propagation of action potentials into the dendritic arbor (14), to impact long term potentiation in CA1 hippocampal neurons (15), to affect neuronal excitability in the visual cortex (16), and to modulate compartmentalization of membrane excitability in distal dendritic spines (17). Fast transient K ϩ currents in cardiac muscles contribute both to myocyte excitability (18) and to the fast repolarization phase of the cardiac action potential (2,8,19,20). Finally, the pharmacological block of channels that carry fast transient currents in gastrointestinal smooth muscle in mice supports the conclusion that the window currents carried by ...

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Regulation of cardiac excitation–contraction coupling by action potential repolarization: role of the transient outward potassium current (I_to)

Cited by 236 publications

References 127 publications

Loss of Cardiomyocyte Integrin-Linked Kinase Produces an Arrhythmogenic Cardiomyopathy in Mice

Loss of Cardiomyocyte Integrin-Linked Kinase Produces an Arrhythmogenic Cardiomyopathy in Mice

Cardiac-specific elevations in thyroid hormone enhance contractility and prevent pressure overload-induced cardiac dysfunction

Mutant Analysis of the Shal (Kv4) Voltage-gated Fast Transient K+ Channel in Caenorhabditis elegans

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Regulation of cardiac excitation–contraction coupling by action potential repolarization: role of the transient outward potassium current (Ito)

Cited by 236 publications

References 127 publications

Loss of Cardiomyocyte Integrin-Linked Kinase Produces an Arrhythmogenic Cardiomyopathy in Mice

Loss of Cardiomyocyte Integrin-Linked Kinase Produces an Arrhythmogenic Cardiomyopathy in Mice

Cardiac-specific elevations in thyroid hormone enhance contractility and prevent pressure overload-induced cardiac dysfunction

Mutant Analysis of the Shal (Kv4) Voltage-gated Fast Transient K+ Channel in Caenorhabditis elegans

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Regulation of cardiac excitation–contraction coupling by action potential repolarization: role of the transient outward potassium current (I_to)