Genetic variation in <i>GNB5</i> causes bradycardia by augmenting the cholinergic response via increased acetylcholine-activated potassium current (<i>I</i>K,ACh)

Veerman, Christiaan C.; Mengarelli, Isabella; Koopman, Charlotte D.; Wilders, Ronald; Amersfoorth, Shirley C van; Bakker, Diane; Wolswinkel, Rianne; Hababa, Mariam; Boer, Teun P. de; Guan, Kaomei; Milnes, James T.; Lodder, Elisabeth M.; Bakkers, Jeroen; Verkerk, Arie O.; Bezzina, Connie R.

doi:10.1242/dmm.037994

Cited by 22 publications

(22 citation statements)

References 48 publications

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“…Overall, the APs of our atrial-like hiPSC-CMs were substantially shorter and had a lower AP plateau than those of our ventricular-like hiPSC-CMs, in qualitative agreement with previous studies on atrial- and ventricular-like hiPSC-CMs ( Marczenke et al, 2017 ; Verkerk et al, 2017 ; Argenziano et al, 2018 ; Cyganek et al, 2018 ; Lemme et al, 2018 ; Veerman et al, 2019 ). There are some quantitative differences in AP parameters with previous studies, but these are likely due to differences in cell lines, differences in differentiation protocols, absence or presence of I K 1 injection, and a different definition of AP plateau amplitude.…”

Section: Discussionsupporting

confidence: 92%

Ultrarapid Delayed Rectifier K+ Channelopathies in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes

Hilderink

Devalla

Bosch

et al. 2020

Front. Cell Dev. Biol.

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Atrial fibrillation (AF) is the most common cardiac arrhythmia. About 5–15% of AF patients have a mutation in a cardiac gene, including mutations in KCNA5 , encoding the K v 1.5 α-subunit of the ion channel carrying the atrial-specific ultrarapid delayed rectifier K + current (I Kur ). Both loss-of-function and gain-of-function AF-related mutations in KCNA5 are known, but their effects on action potentials (APs) of human cardiomyocytes have been poorly studied. Here, we assessed the effects of wild-type and mutant I Kur on APs of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). We found that atrial-like hiPSC-CMs, generated by a retinoic acid-based differentiation protocol, have APs with faster repolarization compared to ventricular-like hiPSC-CMs, resulting in shorter APs with a lower AP plateau. Native I Kur , measured as current sensitive to 50 μM 4-aminopyridine, was 1.88 ± 0.49 (mean ± SEM, n = 17) and 0.26 ± 0.26 pA/pF ( n = 17) in atrial- and ventricular-like hiPSC-CMs, respectively. In both atrial- and ventricular-like hiPSC-CMs, I Kur blockade had minimal effects on AP parameters. Next, we used dynamic clamp to inject various amounts of a virtual I Kur , with characteristics as in freshly isolated human atrial myocytes, into 11 atrial-like and 10 ventricular-like hiPSC-CMs, in which native I Kur was blocked. Injection of I Kur with 100% density shortened the APs, with its effect being strongest on the AP duration at 20% repolarization (APD 20 ) of atrial-like hiPSC-CMs. At I Kur densities < 100% (compared to 100%), simulating loss-of-function mutations, significant AP prolongation and raise of plateau were observed. At I Kur densities > 100%, simulating gain-of-function mutations, APD 20 was decreased in both atrial- and ventricular-like hiPSC-CMs, but only upon a strong increase in I Kur . In ventricular-like hiPSC-CMs, lowering of the plateau resulted in AP shortening. We conclude that a decrease in I Kur , mimicking loss-of-function mutations, has a stronger effect on the AP of hiPSC-CMs than an increase, mimicking gain-of-function mutations, whereas in ventricular-like hiPSC-CMs such increase results in AP shortening, causing their AP morphology to become more atrial-like. Effects of native I Kur modulation on atrial-like hiPSC-CMs are less pronounced than effects of virtual I Kur injection because I Kur density of atrial-like hiPSC-CMs is substantially smaller than that of freshly isolated human atrial myocytes.

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Section: Discussionsupporting

confidence: 92%

Ultrarapid Delayed Rectifier K+ Channelopathies in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes

Hilderink

Devalla

Bosch

et al. 2020

Front. Cell Dev. Biol.

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“…Among the GNB5 pathogenic variants described so far [66,[120][121][122][123][124][125], a mutational hot spot in exon 2, encoding the first WD40 domain and containing 58% of described variants, has been identified ( Figure 2). The evidence of the GNB5 involvement in neuronal and cardiac signaling was confirmed in Gnb5-null zebrafish and mouse models that resulted in neuronal and cardiac phenotypes reminiscent of those of IDDCA patients [63,66,126,127].…”

Section: G Protein Subunit Beta (Gnb5 Gβ 5 )mentioning

confidence: 81%

The Emerging Role of Gβ Subunits in Human Genetic Diseases

Malerba

Nittis

Merla

2019

Cells

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Environmental stimuli are perceived and transduced inside the cell through the activation of signaling pathways. One common type of cell signaling transduction network is initiated by G-proteins. G-proteins are activated by G-protein-coupled receptors (GPCRs) and transmit signals from hormones, neurotransmitters, and other signaling factors, thus controlling a number of biological processes that include synaptic transmission, visual photoreception, hormone and growth factors release, regulation of cell contraction and migration, as well as cell growth and differentiation. G-proteins mainly act as heterotrimeric complexes, composed of alpha, beta, and gamma subunits. In the last few years, whole exome sequencing and biochemical studies have shown causality of disease-causing variants in genes encoding G-proteins and human genetic diseases. This review focuses on the G-protein β subunits and their emerging role in the etiology of genetically inherited rare diseases in humans.

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“…Several studies revealed that PKD1 is not only associated with vascular endothelial growth factor (VEGF) 44 but also exhibited differential expression in the myocardial tissue of a rat model 45 . Moreover, TAGAP 46 , AQP4 47,48 , EPHX2 49 and GNB5 50,51 all provided new insights into the molecular mechanisms through the inflammatory response and apoptosis pathways underlying cardiovascular disease regulation. However, this hypothesis should be further investigated.…”

Section: Discussionmentioning

confidence: 99%

Construction and analysis for differentially expressed long non-coding RNAs and mRNAs in acute myocardial infarction

Song

Luo

et al. 2020

Sci Rep

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Long noncoding RNAs (lncRNAs) are transcripts longer than 200 nucleotides. Some lncRNAs are related to acute myocardial infarction (AMI) and can serve as blood-based biomarkers for AMI detection. To identify whether new lncRNAs participate in AMI, the expression of lncRNAs and mRNAs was analysed by microarray analysis (Agilent human array) with the limma package in R in two series: five paired peripheral blood mononuclear cell (PBMC) samples and four paired plasma samples from different AMI patients. In PBMCs, a total of 2677 upregulated and 458 downregulated lncRNAs were significantly differentially expressed; additionally, 1168 mRNAs were upregulated and 1334 mRNAs were downregulated between the AMI patients and controls. In plasma, we found 41 upregulated and 51 downregulated lncRNAs that were differentially expressed, as well as 9 mRNAs that were upregulated and 9 mRNAs that were downregulated among the two groups. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed using the clusterProfiler package in R, and differentially expressed mRNAs were functionally annotated. The top differentially expressed mRNAs were associated with circadian rhythm, the NF-kB pathway, the p53 pathway and the metabolism pathway. We further performed target gene prediction and coexpression analysis and revealed the interrelationships among the significantly differentially expressed lncRNAs and mRNAs. The expression of four lncRNAs (uc002ddj.1, NR_047662, ENST00000581794.1 and ENST00000509938.1) was validated in the newly diagnosed AMI and control groups by quantitative real-time PCR (qRT-PCR). Our study demonstrated that the clustered expression of lncRNAs between PBMCs and plasma showed tremendous differences. The newly screened lncRNAs may play indispensable roles in the development of AMI, although their biological functions need to be further validated. Acute myocardial infarction (AMI) continues to be the primary cause of disability and death, inducing a major health burden worldwide 1. In the last decade, therapeutic methods, such as coronary intervention, coronary artery bypass surgery and medications, have ameliorated the prognosis of AMI, although its mortality remains nearly as high as before. Thus, it is critical to initiate the early identification and risk stratification of AMI, which would greatly accelerate early intervention 2,3. Advances in genome-wide analyses, especially microarray profiling, play a potential role in discovering novel clinical biomarkers for AMI 4,5. Recently, in the field of AMI, long noncoding RNAs (lncRNAs) have attracted extensive attention. LncRNAs, ranging from 200 nucleotides to >10000 nucleotides in length 6 , lack protein coding capability since they have no open reading frames (ORFs). LncRNAs have been demonstrated to participate in specific physiological and pathological processes in a wide range of cardiovascular diseases (CVDs), such as heart failure 7-9 ,

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Genetic variation in GNB5 causes bradycardia by augmenting the cholinergic response via increased acetylcholine-activated potassium current (IK,ACh)

Cited by 22 publications

References 48 publications

Ultrarapid Delayed Rectifier K+ Channelopathies in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes

Ultrarapid Delayed Rectifier K+ Channelopathies in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes

The Emerging Role of Gβ Subunits in Human Genetic Diseases

Construction and analysis for differentially expressed long non-coding RNAs and mRNAs in acute myocardial infarction

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