beta-Adrenergic modulation of the inwardly rectifying potassium channel in isolated human ventricular myocytes. Alteration in channel response to beta-adrenergic stimulation in failing human hearts.

Koumi, Shin-ichi; Backer, Carl L.; Arentzen, C. E.; Satō, Ryōichi

doi:10.1172/jci118358

Cited by 91 publications

(50 citation statements)

References 53 publications

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“…The increased I K1 density in the I K1 -enhanced iPS-CMs was similar in magnitude to that reported in human ventricular myocytes (12). In accordance with most mammalian animal models, including human ventricular myocytes, APD shortens as pacing frequency increases (14,24) and the APD values we measured are similar to the previously reported range for human ventricular myocytes (15,16,22).…”

Section: Discussionsupporting

confidence: 90%

“…When compared with previous reports of endogenous I K1 in iCell cardiomyocytes (18), I K1 -enhanced iPS-CMs density at depolarized voltages was increased approximately fivefold. On the other hand, the inward (Ϫ120 mV) and outward (Ϫ60 mV) current densities of I K1 -enhanced iPS-CMs are similar in magnitude to adult human I K1 reported by Koumi et al (12).…”

Section: K1 From I K1 -Enhanced Ips-cmssupporting

confidence: 84%

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I_K1-enhanced human-induced pluripotent stem cell-derived cardiomyocytes: an improved cardiomyocyte model to investigate inherited arrhythmia syndromes

Vaidyanathan

Markandeya

Kamp

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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Vaidyanathan R, Markandeya YS, Kamp TJ, Makielski JC, January CT, Eckhardt LL. IK1-enhanced human-induced pluripotent stem cell-derived cardiomyocytes: an improved cardiomyocyte model to investigate inherited arrhythmia syndromes. Am J Physiol Heart Circ Physiol 310: H1611-H1621, 2016. First published April 8, 2016; doi:10.1152/ajpheart.00481.2015.-Currently available induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs) do not ideally model cellular mechanisms of human arrhythmic disease due to lack of a mature action potential (AP) phenotype. In this study, we create and characterize iPS-CMs with an electrically mature AP induced by potassium inward rectifier (IK1) enhancement. The advantages of IK1-enhanced iPS-CMs include the absence of spontaneous beating, stable resting membrane potentials at approximately Ϫ80 mV and capability for electrical pacing. Compared with unenhanced, IK1-enhanced iPS-CMs calcium transient amplitudes were larger (P Ͻ 0.05) with a typical staircase pattern. IK1-enhanced iPS-CMs demonstrated a twofold increase in cell size and membrane capacitance and increased DNA synthesis compared with control iPS-CMs (P Ͻ 0.05). Furthermore, IK1-enhanced iPS-CMs expressing the F97C-CAV3 long QT9 mutation compared with wild-type CAV3 demonstrated an increase in AP duration and late sodium current. I K1-enhanced iPSCMs represent a more mature cardiomyocyte model to study arrhythmia mechanisms. arrhythmia; potassium ion channel; LQTS; iPS-CM NEW & NOTEWORTHY Ik1-enhanced induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs) more closely represent the cell size, structure, multinucleation, electrophysiology, and calcium handling properties of adult human cardiomyocytes. These I K1-enhanced iPS-CMs will permit advanced studies of arrhythmia mechanisms such as rotor and reentry generation in plated iPS-CMs or drug safety testing due to the mature cellular phenotype.INDUCED PLURIPOTENT STEM (iPS) cells have opened new avenues to investigate many human diseases (33). Patient-specific iPSderived cardiomyocytes (iPS-CMs) have been used to investigate inherited arrhythmia syndromes such as long QT syndrome (LQTS) and catecholeminergic polymorphic ventricular tachycardia (9,21,31,34). These proof of concept studies have recapitulated some characteristic features of human disease (8, 23). However, despite advances in differentiation and culturing techniques, currently available iPS-CMs have several features of immature cardiomyocytes, which limit their application for modeling cellular arrhythmia mechanisms and inherited arrhythmic disease. The electrophysiological limitations occur predominately due to action potential (AP) diastolic properties including a relatively depolarized resting membrane potential and spontaneous automaticity due to a small inward rectifier (I K1 ) density and unopposed pacemaker current (I f ) (5, 18). In turn, this results in partial inactivation of ion channels such as the cardiac sodium channel to reduce current (I Na ) amplitude. Automaticity also interferes w...

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Section: Discussionsupporting

confidence: 90%

Section: K1 From I K1 -Enhanced Ips-cmssupporting

confidence: 84%

I_K1-enhanced human-induced pluripotent stem cell-derived cardiomyocytes: an improved cardiomyocyte model to investigate inherited arrhythmia syndromes

Vaidyanathan

Markandeya

Kamp

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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“…The activation of PKA reduces I K1 density in cardiac myocytes because of a change in the channel open probability (32). Terminal residues at the Kir2.x C terminus contain a PKA consensus sequence, RRXS that overlaps the PDZ domain binding sequence.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Cardiac Inward Rectifier Potassium Current (IK1) by Synapse-associated Protein-97

Vaidyanathan

Taffet

Vikstrom

et al. 2010

Journal of Biological Chemistry

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Synapse-associated protein-97 (SAP97) is a membrane-associated guanylate kinase scaffolding protein expressed in cardiomyocytes. SAP97 has been shown to associate and modulate voltage-gated potassium (Kv) channel function. In contrast to Kv channels, little information is available on interactions involving SAP97 and inward rectifier potassium (Kir2.x) channels that underlie the classical inward rectifier current, I K1 . To investigate the functional effects of silencing SAP97 on I K1 in adult rat ventricular myocytes, SAP97 was silenced using an adenoviral short hairpin RNA vector. Western blot analysis showed that SAP97 was silenced by ϳ85% on day 3 post-infection. Immunostaining showed that Kir2.1 and Kir2.2 co-localize with SAP97. Co-immunoprecipitation (co-IP) results demonstrated that Kir2.x channels associate with SAP97. Voltage clamp experiments showed that silencing SAP97 reduced I K1 whole cell density by ϳ55%. I K1 density at ؊100 mV was ؊1.45 ؎ 0.15 pA/picofarads (n ‫؍‬ 6) in SAP97-silenced cells as compared with ؊3.03 ؎ 0.37 pA/picofarads (n ‫؍‬ 5) in control cells. Unitary conductance properties of I K1 were unaffected by SAP97 silencing. The major mechanism for the reduction of I K1 density appears to be a decrease in Kir2.x channel abundance. Furthermore, SAP97 silencing impaired I K1 regulation by ␤ 1 -adrenergic receptor (␤1-AR) stimulation. In control, isoproterenol reduced I K1 amplitude by ϳ75%, an effect that was blunted following SAP97 silencing. Our co-IP data show that ␤1-AR associates with SAP97 and Kir2.1 and also that Kir2.1 co-IPs with protein kinase A and ␤1-AR. SAP97 immunolocalizes with protein kinase A and ␤1-AR in the cardiac myocytes. Our results suggest that in cardiac myocytes SAP97 regulates surface expression of channels underlying I K1 , as well as assembles a signaling complex involved in ␤1-AR regulation of I K1 .In the heart, inward rectifier potassium current (I K1 ) plays a key role in stabilizing the resting membrane potential, determining the excitation threshold, and initiating the final repolarization phase of the action potential. Inward rectifier potassium channel subfamily 2 members (Kir2.1, Kir2.2, and Kir2.3 (Kir2.x) 3 ) are the molecular correlates of I K1 in the heart (1, 2). In contrast to other cardiac ion channels, relatively little information is available on protein-protein interactions involving Kir2.x channels that are important for their function. We have shown recently that Kir2.3 is regulated by synapse-associated protein 97 (SAP97) in a heterologous expression system, but it is not known if cardiac Kir2.x channels are regulated in a similar manner in situ (3).SAP97 belongs to the membrane-associated guanylate kinase family of proteins and is ubiquitously expressed in the heart (4). The membrane-associated guanylate kinase family of proteins are involved in the trafficking and assembly of proteins into macromolecular signaling complexes (5). They have protein-protein interaction domains such as PDZ (PSD-95, disclarge, ZO-1) domains, guanylate k...

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“…Sympathetic stimulation of the heart is well known to be associated with the initiation of cardiac arrhythmias with ␤-adrenoceptor activation known to play a particularly important role (42). Acute ␤-adrenergic stimulation enhances a variety of cardiac ionic currents, including I Ks (34), I Ca L (32), and cAMP-dependent Cl Ϫ current (10), and reduces I K1 (14). Much less is known about the effects on cardiac ion channels of longer term exposure to ␤-adrenergic agonists.…”

Section: Discussionmentioning

confidence: 99%

Effects of sustained β-adrenergic stimulation on ionic currents of cultured adult guinea pig cardiomyocytes

Zhang

Wang

Nattel

2002

American Journal of Physiology-Heart and Circulatory Physiology

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Short-term stimulation of β-receptors is known to affect cardiac ion channels; however, the impact of longer-term stimulation on intrinsic channel function is poorly understood. To evaluate this, cultured guinea pig ventricular myocytes were exposed to isoproterenol (10 nM), vehicle, or isoproterenol plus propranolol (1 μM) for 48 h. Sustained exposure to isoproterenol decreased the density of the inward rectifier ( I K1), slow delayed rectifier ( I Ks), and L-type Ca2+( I Ca L) currents, effects that were fully prevented by propranolol. Changes in K+ currents were prevented by the β1-selective antagonist CGP-20712A, unaffected by the β2-antagonist ICI-118,551, and mimicked by the membrane-permeable cAMP analog 8-bromo-cAMP. Isoproterenol did not alter the current-voltage relationship of the K+currents but increased the density of T-type Ca2+ current ( I Ca T) and thereby increased the proportion of the total Ca2+ current at more negative potentials. We conclude that sustained exposure to isoproterenol reduces I K1, I Ks, and I Ca L density and increases the density of I Ca T. The direct ionic current remodeling effects of sustained β-adrenoceptor stimulation resemble changes reported with heart failure and may be important in arrhythmogenic ionic remodeling.

show abstract

beta-Adrenergic modulation of the inwardly rectifying potassium channel in isolated human ventricular myocytes. Alteration in channel response to beta-adrenergic stimulation in failing human hearts.

Cited by 91 publications

References 53 publications

I_K1-enhanced human-induced pluripotent stem cell-derived cardiomyocytes: an improved cardiomyocyte model to investigate inherited arrhythmia syndromes

I_K1-enhanced human-induced pluripotent stem cell-derived cardiomyocytes: an improved cardiomyocyte model to investigate inherited arrhythmia syndromes

Regulation of Cardiac Inward Rectifier Potassium Current (IK1) by Synapse-associated Protein-97

Effects of sustained β-adrenergic stimulation on ionic currents of cultured adult guinea pig cardiomyocytes

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