The interaction of caveolin 3 protein with the potassium inward rectifier channel Kir2.1. PHYSIOLOGY AND PATHOLOGY RELATED TO LONG QT SYNDROME 9 (LQT9).

Vaidyanathan, Ravi; Vega, Amanda L.; Song, Chunhua; Zhou, Qing; Tan, Bi Hua; Berger, Stuart; Makielski, Jonathan C.; Eckhardt, Lee L.

doi:10.1074/jbc.a112.435370

Cited by 12 publications

(20 citation statements)

References 30 publications

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“…This decision was made due to the 25-30% variability in Kir2.1 current density seen postviral infection. This variability did not affect the variability of resting membrane potential in Kir2.1-infected iPS-CMs but is the same variability by which F97C-CAV3 decreases Kir2.1 current density in heterologous cell model (28). We are currently pursuing new methods to address this degree of variability.…”

Section: H1619 Ips-cm Model For Investigating Complex Inherited Arrhymentioning

confidence: 85%

“…Immunocytochemistry was performed as previously described (28). IK1-enhanced iPS-CMs and viral controlinfected iPS-CMs were plated on coverslips and fixed using 4% formaldehyde and permeabilized with 0.1% Triton X-100.…”

Section: Ips-cms Ips-cms (Icells) Were Obtained From Cellular Dynamicsmentioning

confidence: 99%

“…Therefore, we expected to see a relative increase in I Na-P and I Na-L in I K1 enhancement. However, F97C-CAV3 plus I K1 enhancement would not result in an increase in I Na-P but will increase I Na-L since this mutation has been shown to decrease Kir2.1 trafficking, thus Na V 1.5 expression modulation would not occur (3,28). I K1 enhancement in patient-specific cell lines or iPS-CMs modified by CRISPR technology is a logical extension of this work and may aid in this disease characterization as well as therapeutics testing.…”

Section: H1618mentioning

confidence: 99%

“…We previously reported using a heterologous expression model (HEK293 cells) that CAV3 LQT9 mutations increase late I Na (I Na-L ) without affecting peak I Na (I Na-P ) density and steady-state activation or inactivation (3,30) and reduced I K1 density by decreasing surface membrane expression of Kir2.1 (28). Other groups have attempted to compensate for the small density of I K1 in iPS-CMs by electronic addition of I K1 or viral infection of Kir2.1 (2,17), but, to date, augmentation of I K1 has not been systematically studied for its effects on AP characteristics, membrane currents, or cardiomyocyte growth.…”

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confidence: 99%

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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: H1619 Ips-cm Model For Investigating Complex Inherited Arrhymentioning

confidence: 85%

Section: Ips-cms Ips-cms (Icells) Were Obtained From Cellular Dynamicsmentioning

confidence: 99%

Section: H1618mentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…71,72 CAV1 is an important membrane protein, which plays a role in cellular signalling, and has been demonstrated to interact with ion channels, including HCN4 and KCNN3. [73][74][75][76] In addition to the variants identified in the aforementioned GWAS for AF, common variants that have previously been implicated in GWAS for Brugada syndrome have also been demonstrated to influence risk in AF. AF is commonly observed as a co-existing condition in pedigrees with Brugada syndrome.…”

Section: Common Genetic Variants and Atrial Fibrillation In The Genermentioning

confidence: 99%

Genetic Discoveries in Atrial Fibrillation and Implications for Clinical Practice

Mahida

2014

Arrhythmia &Amp; Electrophysiology Review

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Linkage analysis and candidate-gene sequencing have identified multiple mutations in monogenic AF families and isolated AF cases. 2-31Linkage analysis involves performing genotyping of markers distributed AbstractAtrial fibrillation (AF) is an arrhythmia with a genetic basis. Over the past decade, rapid advances in genotyping technology have revolutionised research regarding the genetic basis of AF. While AF genetics research was previously largely restricted to familial forms of AF, recent studies have begun to characterise the genetic architecture underlying the form of AF encountered in everyday clinical practice. These discoveries could have a significant impact on the management of AF. However, much work remains before genetic findings can be translated to clinical practice. This review summarises results of studies in AF genetics to date and discusses the potential implications of these findings in clinical practice. KeywordsAtrial fibrillation, genetics, familial AF, linkage analysis, candidate gene association studies, genome-wide association studies, risk stratification Disclosure: The author has no conflicts of interest to declare.

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The caveolin‐3 P104L mutation in LGMD‐1C patients inhibits non‐insulin‐stimulated glucose metabolism and growth but promotes myocyte proliferation

Shang

Chen

Xian

et al. 2019

Cell Biology International

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The caveolin‐3 (CAV3) protein is known to be specifically expressed in various myocytes, and skeletal muscle consumes most of the blood glucose as an energy source to maintain normal cell metabolism and function. The P104L mutation in the coding sequence of the human CAV3 gene leads to autosomal dominant disease limb‐girdle muscular dystrophy type 1C (LGMD‐1C). We previously reported that C2C12 cells transiently transfected with the P104L CAV3 mutant exhibited decreased glucose uptake and glycogen synthesis after insulin stimulation. The present study aimed to examine whether the P104L mutation affects C2C12 cell glucose metabolism, growth, and proliferation without insulin stimulation. C2C12 cells stably transfected with CAV3‐P104L were established, and biochemical assays, western blot analysis and confocal microscopy were used to observe glucose metabolism as well as cell growth and proliferation and to determine the effect of the P104L mutation on the PI3K/Akt signaling pathway. Without insulin stimulation, C2C12 cells stably transfected with the P104L CAV3 mutant exhibited decreased glucose uptake and glycogen synthesis, decreased CAV3 expression and reduced localization of CAV3 and GLUT4 on the cell membrane. The P104L mutant significantly reduced the cell diameters, but accelerated cell proliferation. Akt phosphorylation was inhibited, and protein expression of GLUT4, p‐GSK3β, and p‐p70s6K, which are molecules downstream of Akt, was significantly decreased. The CAV3‐P104L mutation inhibits glycometabolism and cell growth but accelerates C2C12 cell proliferation by reducing CAV3 protein expression and cell membrane localization, which may contribute to the pathogenesis of LGMD‐1C.

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The interaction of caveolin 3 protein with the potassium inward rectifier channel Kir2.1. PHYSIOLOGY AND PATHOLOGY RELATED TO LONG QT SYNDROME 9 (LQT9).

Abstract: Authors are urged to introduce these corrections into any reprints they distribute. Secondary (abstract) services are urged to carry notice of these corrections as prominently as they carried the original abstracts.

Cited by 12 publications

References 30 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

Genetic Discoveries in Atrial Fibrillation and Implications for Clinical Practice

The caveolin‐3 P104L mutation in LGMD‐1C patients inhibits non‐insulin‐stimulated glucose metabolism and growth but promotes myocyte proliferation

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