Mechanisms and Alterations of Cardiac Ion Channels Leading to Disease: Role of Ankyrin-B in Cardiac Function

Amuzescu

2021

Sci Rep

Myocardium transcriptomes of left and right atria and ventricles from four adult male C57Bl/6j mice were profiled with Agilent microarrays to identify the differences responsible for the distinct functional roles of the four heart chambers. Female mice were not investigated owing to their transcriptome dependence on the estrous cycle phase. Out of the quantified 16,886 unigenes, 15.76% on the left side and 16.5% on the right side exhibited differential expression between the atrium and the ventricle, while 5.8% of genes were differently expressed between the two atria and only 1.2% between the two ventricles. The study revealed also chamber differences in gene expression control and coordination. We analyzed ion channels and transporters, and genes within the cardiac muscle contraction, oxidative phosphorylation, glycolysis/gluconeogenesis, calcium and adrenergic signaling pathways. Interestingly, while expression of Ank2 oscillates in phase with all 27 quantified binding partners in the left ventricle, the percentage of in-phase oscillating partners of Ank2 is 15% and 37% in the left and right atria and 74% in the right ventricle. The analysis indicated high interventricular synchrony of the ion channels expressions and the substantially lower synchrony between the two atria and between the atrium and the ventricle from the same side.

Section: Discussionsupporting

confidence: 66%

Section: Resultsmentioning

confidence: 99%

Transcriptomic uniqueness and commonality of the ion channels and transporters in the four heart chambers

Amuzescu

2021

Sci Rep

“…The latter was predicted as deleterious ( Table 2 ). Furthermore, ANK2 loss-of-function variants were extensively related with inherited cardiac arrhythmias [ 20 ], even with BrS [ 21 ], although this relationship is currently under debate [ 22 ].…”

Section: Resultsmentioning

confidence: 99%

Zfhx3 Transcription Factor Represses the Expression of SCN5A Gene and Decreases Sodium Current Density (INa)

Rubio-Alarcón

Cámara-Checa

Dago

et al. 2021

IJMS

The ZFHX3 and SCN5A genes encode the zinc finger homeobox 3 (Zfhx3) transcription factor (TF) and the human cardiac Na+ channel (Nav1.5), respectively. The effects of Zfhx3 on the expression of the Nav1.5 channel, and in cardiac excitability, are currently unknown. Additionally, we identified three Zfhx3 variants in probands diagnosed with familial atrial fibrillation (p.M1260T) and Brugada Syndrome (p.V949I and p.Q2564R). Here, we analyzed the effects of native (WT) and mutated Zfhx3 on Na+ current (INa) recorded in HL-1 cardiomyocytes. ZFHX3 mRNA can be detected in human atrial and ventricular samples. In HL-1 cardiomyocytes, transfection of Zfhx3 strongly reduced peak INa density, while the silencing of endogenous expression augmented it (from −65.9 ± 8.9 to −104.6 ± 10.8 pA/pF; n ≥ 8, p < 0.05). Zfhx3 significantly reduced the transcriptional activity of human SCN5A, PITX2, TBX5, and NKX25 minimal promoters. Consequently, the mRNA and/or protein expression levels of Nav1.5 and Tbx5 were diminished (n ≥ 6, p < 0.05). Zfhx3 also increased the expression of Nedd4-2 ubiquitin-protein ligase, enhancing Nav1.5 proteasomal degradation. p.V949I, p.M1260T, and p.Q2564R Zfhx3 produced similar effects on INa density and time- and voltage-dependent properties in WT. WT Zfhx3 inhibits INa as a result of a direct repressor effect on the SCN5A promoter, the modulation of Tbx5 increasing on the INa, and the increased expression of Nedd4-2. We propose that this TF participates in the control of cardiac excitability in human adult cardiac tissue.

“…Ankyrin-B is expressed within the nodal cells, the cardiac conduction system, and atrial and ventricular myocytes, where it interacts with several channels and transporters important for Ca 2+ handling in cardiomyocytes, including the Na + /Ca 2+ exchanger (NCX), Na + /K + ATPase (NKA) and inositol-1,4,5-triphosphate receptor (IP 3 R) [ 15 , 28 ] as well as the protein phosphatase, PP2A ( Figure 2 and Figure 3 ) [ 29 , 30 ]. In SAN myocytes, ankyrin-B has also been found to associate with Ca v 1.3, a predominantly neuronal L-type Ca 2+ channel that is an important determinant of spontaneous diastolic depolarization phase of the SAN action potential [ 31 ].…”

Section: Ankyrins In the Cardiac Conduction Systemmentioning

confidence: 99%

Regulation of Cardiac Conduction and Arrhythmias by Ankyrin/Spectrin-Based Macromolecular Complexes

Nassal

Min

et al. 2021

JCDD

The cardiac conduction system is an extended network of excitable tissue tasked with generation and propagation of electrical impulses to signal coordinated contraction of the heart. The fidelity of this system depends on the proper spatio-temporal regulation of ion channels in myocytes throughout the conduction system. Importantly, inherited or acquired defects in a wide class of ion channels has been linked to dysfunction at various stages of the conduction system resulting in life-threatening cardiac arrhythmia. There is growing appreciation of the role that adapter and cytoskeletal proteins play in organizing ion channel macromolecular complexes critical for proper function of the cardiac conduction system. In particular, members of the ankyrin and spectrin families have emerged as important nodes for normal expression and regulation of ion channels in myocytes throughout the conduction system. Human variants impacting ankyrin/spectrin function give rise to a broad constellation of cardiac arrhythmias. Furthermore, chronic neurohumoral and biomechanical stress promotes ankyrin/spectrin loss of function that likely contributes to conduction disturbances in the setting of acquired cardiac disease. Collectively, this review seeks to bring attention to the significance of these cytoskeletal players and emphasize the potential therapeutic role they represent in a myriad of cardiac disease states.