Inherited Cardiac Arrhythmia Syndromes: Focus on Molecular Mechanisms Underlying TRPM4 Channelopathies

Amarouch, Mohamed Yassine; El-Hilaly, Jaouad

doi:10.1155/2020/6615038

Cited by 22 publications

(19 citation statements)

References 86 publications

(57 reference statements)

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“…Much remains to be done also on the mechanisms underlying these interactions, which according to the available literature can be mediated by: (1) direct activation by chemical components released by PM, (2) activation by ROS induced by the action of PM on other cellular targets, (3) increase in [Ca 2+ ] I induced by PM, and (4) detection of perturbations induced in the plasma membrane. Also crucial is to determine the pathophysiological relevance of PM-TRP channels in vivo, especially in the context of human genetic or acquired health conditions that may increase the susceptibility to PM actions [ 39 , 52 , 114 , 115 , 116 , 117 , 118 ]. Finally, future studies may reveal exciting possibilities of using engineered nanoparticles for targeted drug delivery to modulate TRP channel function and other biomedical applications.…”

Section: Discussionmentioning

confidence: 99%

TRP Channels as Cellular Targets of Particulate Matter

Milici

Talavera

2021

IJMS

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Particulate matter (PM) is constituted by particles with sizes in the nanometer to micrometer scales. PM can be generated from natural sources such as sandstorms and wildfires, and from human activities, including combustion of fuels, manufacturing and construction or specially engineered for applications in biotechnology, food industry, cosmetics, electronics, etc. Due to their small size PM can penetrate biological tissues, interact with cellular components and induce noxious effects such as disruptions of the cytoskeleton and membranes and the generation of reactive oxygen species. Here, we provide an overview on the actions of PM on transient receptor potential (TRP) proteins, a superfamily of cation-permeable channels with crucial roles in cell signaling. Their expression in epithelial cells and sensory innervation and their high sensitivity to chemical, thermal and mechanical stimuli makes TRP channels prime targets in the major entry routes of noxious PM, which may result in respiratory, metabolic and cardiovascular disorders. On the other hand, the interactions between TRP channel and engineered nanoparticles may be used for targeted drug delivery. We emphasize in that much further research is required to fully characterize the mechanisms underlying PM-TRP channel interactions and their relevance for PM toxicology and biomedical applications.

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Section: Discussionmentioning

confidence: 99%

TRP Channels as Cellular Targets of Particulate Matter

Milici

Talavera

2021

IJMS

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“…The pathogenic variants p.I4855M and deletion of exon 3 in the RYR2 gene have been associated with the rare syndrome of left ventricular non-compaction (LVNC) overlap and CPVT, presenting a high lethality [ 85 ]. Pathogenic variants in the TRPM4 gene, both gain and loss of function, have been identified in patients with different forms of cardiac disorder including conduction defects, BrS and LQTS [ 77 ]. The PKP2 gene, the main gene mutated in arrhythmogenic cardiomyopathy (ACM), has been recently associated with BrS and CPVT.…”

Section: Genetic Overlapmentioning

confidence: 99%

Clinical Genetics of Inherited Arrhythmogenic Disease in the Pediatric Population

et al. 2022

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Sudden death is a rare event in the pediatric population but with a social shock due to its presentation as the first symptom in previously healthy children. Comprehensive autopsy in pediatric cases identify an inconclusive cause in 40–50% of cases. In such cases, a diagnosis of sudden arrhythmic death syndrome is suggested as the main potential cause of death. Molecular autopsy identifies nearly 30% of cases under 16 years of age carrying a pathogenic/potentially pathogenic alteration in genes associated with any inherited arrhythmogenic disease. In the last few years, despite the increasing rate of post-mortem genetic diagnosis, many families still remain without a conclusive genetic cause of the unexpected death. Current challenges in genetic diagnosis are the establishment of a correct genotype–phenotype association between genes and inherited arrhythmogenic disease, as well as the classification of variants of uncertain significance. In this review, we provide an update on the state of the art in the genetic diagnosis of inherited arrhythmogenic disease in the pediatric population. We focus on emerging publications on gene curation for genotype–phenotype associations, cases of genetic overlap and advances in the classification of variants of uncertain significance. Our goal is to facilitate the translation of genetic diagnosis to the clinical area, helping risk stratification, treatment and the genetic counselling of families.

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“…Four TRPM4 mutations were found to be present in cases of sudden cardiac death [58]. A recent review summarizes the role of TRPM4 mutations in inherited cardiac arrhythmia syndromes [59].…”

Section: Effects Of Cba On Short-term Variability Of Repolarizationmentioning

confidence: 99%

Electrophysiological Effects of the Transient Receptor Potential Melastatin 4 Channel Inhibitor (4-Chloro-2-(2-chlorophenoxy)acetamido) Benzoic Acid (CBA) in Canine Left Ventricular Cardiomyocytes

Dienes

Hézsô

Kiss

et al. 2021

IJMS

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Transient receptor potential melastatin 4 (TRPM4) plays an important role in many tissues, including pacemaker and conductive tissues of the heart, but much less is known about its electrophysiological role in ventricular myocytes. Our earlier results showed the lack of selectivity of 9-phenanthrol, so CBA ((4-chloro-2-(2-chlorophenoxy)acetamido) benzoic acid) was chosen as a new, potentially selective inhibitor. Goal: Our aim was to elucidate the effect and selectivity of CBA in canine left ventricular cardiomyocytes and to study the expression of TRPM4 in the canine heart. Experiments were carried out in enzymatically isolated canine left ventricular cardiomyocytes. Ionic currents were recorded with an action potential (AP) voltage-clamp technique in whole-cell configuration at 37 °C. An amount of 10 mM BAPTA was used in the pipette solution to exclude the potential activation of TRPM4 channels. AP was recorded with conventional sharp microelectrodes. CBA was used in 10 µM concentrations. Expression of TRPM4 protein in the heart was studied by Western blot. TRPM4 protein was expressed in the wall of all four chambers of the canine heart as well as in samples prepared from isolated left ventricular cells. CBA induced an approximately 9% reduction in AP duration measured at 75 and 90% of repolarization and decreased the short-term variability of APD90. Moreover, AP amplitude was increased and the maximal rates of phase 0 and 1 were reduced by the drug. In AP clamp measurements, CBA-sensitive current contained a short, early outward and mainly a long, inward current. Transient outward potassium current (Ito) and late sodium current (INa,L) were reduced by approximately 20 and 47%, respectively, in the presence of CBA, while L-type calcium and inward rectifier potassium currents were not affected. These effects of CBA were largely reversible upon washout. Based on our results, the CBA induced reduction of phase-1 slope and the slight increase of AP amplitude could have been due to the inhibition of Ito. The tendency for AP shortening can be explained by the inhibition of inward currents seen in AP-clamp recordings during the plateau phase. This inward current reduced by CBA is possibly INa,L, therefore, CBA is not entirely selective for TRPM4 channels. As a consequence, similarly to 9-phenanthrol, it cannot be used to test the contribution of TRPM4 channels to cardiac electrophysiology in ventricular cells, or at least caution must be applied.

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Inherited Cardiac Arrhythmia Syndromes: Focus on Molecular Mechanisms Underlying TRPM4 Channelopathies

Cited by 22 publications

References 86 publications

TRP Channels as Cellular Targets of Particulate Matter

TRP Channels as Cellular Targets of Particulate Matter

Clinical Genetics of Inherited Arrhythmogenic Disease in the Pediatric Population

Electrophysiological Effects of the Transient Receptor Potential Melastatin 4 Channel Inhibitor (4-Chloro-2-(2-chlorophenoxy)acetamido) Benzoic Acid (CBA) in Canine Left Ventricular Cardiomyocytes

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