There has been a significant progress in our understanding of the molecular mechanisms by which calcium (Ca 2+ ) ions mediate various types of cardiac arrhythmias. A growing list of inherited gene defects can cause potentially lethal cardiac arrhythmia syndromes, including catecholaminergic polymorphic ventricular tachycardia, congenital long QT syndrome, and hypertrophic cardiomyopathy. In addition, acquired deficits of multiple Ca 2+ -handling proteins can contribute to the pathogenesis of arrhythmias in patients with various types of heart disease. In this review article, we will first review the key role of Ca 2+ in normal cardiac function—in particular, excitation–contraction coupling and normal electric rhythms. The functional involvement of Ca 2+ in distinct arrhythmia mechanisms will be discussed, followed by various inherited arrhythmia syndromes caused by mutations in Ca 2+ -handling proteins. Finally, we will discuss how changes in the expression of regulation of Ca 2+ channels and transporters can cause acquired arrhythmias, and how these mechanisms might be targeted for therapeutic purposes.

Calcium Signaling and Cardiac Arrhythmias.

The aggregation-induced electrochemiluminescence (AIECL) of carboranyl carbazoles in aqueous media was investigated for the first time. Quantum yields, morphologies, and particle sizes were observed to determine the electrochemiluminescence (ECL) performance of these aggregated organic dots (ODs). All compounds exhibit much higher ECL stability and intensity than the carborane-free compound, demonstrating the essential role of the carboranyl motif. Moreover, the results of cyclic voltammetry (CV) suggest that oxidation/reduction reactions take place at the carboranyl motif. The excited states of ODs were proposed to be generated by the mechanism of surface state transitions. More importantly, these compounds show a reductive-oxidative mechanism in contrast to other organic materials that show oxidative-reductive mechanisms. Our experiments and data have established the relation between AIE organic structures and ECL properties that has a strong potential for biological and diagnostic applications.

Aggregation-Induced Electrochemiluminescence of Carboranyl Carbazoles in Aqueous Media

The main inherited cardiac arrhythmias are long QT syndrome, short QT syndrome, catecholaminergic polymorphic ventricular tachycardia and Brugada syndrome. These rare diseases are often the underlying cause of sudden cardiac death in young individuals and result from mutations in several genes encoding ion channels or proteins involved in their regulation. The genetic defects lead to alterations in the ionic currents that determine the morphology and duration of the cardiac action potential, and individuals with these disorders often present with syncope or a life-threatening arrhythmic episode. The diagnosis is based on clinical presentation and history, the characteristics of the electrocardiographic recording at rest and during exercise and genetic analyses. Management relies on pharmacological therapy, mostly β-adrenergic receptor blockers (specifically, propranolol and nadolol) and sodium and transient outward current blockers (such as quinidine), or surgical interventions, including left cardiac sympathetic denervation and implantation of a cardioverter-defibrillator. All these arrhythmias are potentially life-threatening and have substantial negative effects on the quality of life of patients. Future research should focus on the identification of genes associated with the diseases and other risk factors, improved risk stratification and, in particular for Brugada syndrome, effective therapies.

Inherited cardiac arrhythmias.

Electrified solid/liquid interfaces are the key to many physicochemical processes in a myriad of areas including electrochemistry and colloid science. With tremendous efforts devoted to this topic, it is unexpected that molecular-level understanding of electric double layers is still lacking. Particularly, it is perplexing why compact Helmholtz layers often show bell-shaped differential capacitances on metal electrodes, as this would suggest a negative capacitance in some layer of interface water. Here, we report state-of-the-art ab initio molecular dynamics simulations of electrified Pt(111)/water interfaces, aiming at unraveling the structure and capacitive behavior of interface water. Our calculation reproduces the bell-shaped differential Helmholtz capacitance and shows that the interface water follows the Frumkin adsorption isotherm when varying the electrode potential, leading to a peculiar negative capacitive response. Our work provides valuable insight into the structure and capacitance of interface water, which can help understand important processes in electrocatalysis and energy storage in supercapacitors.

Molecular origin of negative component of Helmholtz capacitance at electrified Pt(111)/water interface

The growing application of nanotechnology causes the release of engineered nanoparticles (NPs) into aquatic environments. With increasing concerns over the potential effect of NPs on aquatic organisms, investigations on NP toxicity to algae are rising. To date, the overall algal response to cope with NP toxicity is still uncertain. In this review, a meta-analysis was conducted to quantitatively assess the toxicity mechanisms dominated by oxidative stress. The reactive oxygen species elevated by 90% caused retarded algal growth by reduction (38%) in cell density, and NP toxicity was strongly dependent on the NP type and dose. Specifically, the mechanisms of NP toxicity were discussed in different “omics” levels. Further, we summarized the current knowledge and mechanisms of defense strategies, including formation of a protective bio-barrier and adjustment in intracellular processes (internalization, transformation and compartmentation) to decrease cellular NP concentrations. Based on the response patterns of algae to NPs, we addressed the possibility of NP application for algal bloom control. A systematic understanding of algal response mechanisms to NPs will help develop safe and sustainable nanotechnology in aquatic ecosystems.

Algae response to engineered nanoparticles: current understanding, mechanisms and implications

Recent studies show that polyunsaturated fatty acids (PUFAs) modulate acid-sensing ion channels (ASICs) by activating them in physiological pH. However, the binding site for PUFAs on ASICs has been a subject of controversy, and molecular mechanism of this modulation remains unknown. Conflicting reports suggest two distinct binding sites for PUFAs on ASIC3, R63 and R65&R68, respectively. To address this issue, we employed molecular docking and molecular dynamic (MD) simulations to investigate the binding of arachidonoyl glycine (AG) and docosahexaenoic acid (DHA) to ASIC3 in multiple functional states. 

The state-dependent binding of polyunsaturated fatty acids and a novel modulation mechanism on ASIC channels

BPS2025 - DHA differentially modulates ASIC3 through interactions with transmembrane residues

Polyunsaturated fatty acids (PUFAs) and their analogs play a significant role in modulating the activity of diverse ion channels, and recent studies show that these lipids potentiate acid-sensing ion channels (ASICs), leading to increased activity. The potentiation of the channel stems from multiple gating changes, but the exact mechanism of these effects remains uncertain. We posit a mechanistic explanation for one of these changes in channel function, the increase in the maximal current, by applying a combination of electrophysiology and all-atom molecular dynamics simulations on the open-state hASIC3. Microsecond-scale simulations were performed on open-state hASIC3 in the absence and presence of a PUFA, docosahexaenoic acid (DHA), and a PUFA analog, N-arachidonyl glycine (AG). Intriguingly, our simulations in the absence of PUFA or PUFA analogs reveal that a tail from the membrane phospholipid POPC inserts itself into the pore of the channel through lateral fenestrations on the sides of the transmembrane segments, obstructing ion permeation through the channel. The binding of either DHA or AG prevented POPC from accessing the pore in our simulations, relieving the block of ionic conduction by phospholipids. Finally, we use the single-channel recording to show that DHA increases the amplitude of the single-channel currents in ASIC3, which is consistent with our hypothesis that PUFAs relieve the pore block of the channel induced by POPCs. Together, these findings offer a potential mechanistic explanation of how PUFAs modulate ASIC maximal current, revealing a novel mechanism of action for PUFA-induced modulation of ion channels.

Molecular Insights into Single Chain Lipid Modulation of Acid-Sensing Ion Channel 3

https://www.heartrhythmjournal.com/article/S1547-5271(17)31438-8/pdf

EL20, a potent antiarrhythmic compound, selectively inhibits calmodulin-deficient ryanodine receptor type 2

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The state-dependent binding of polyunsaturated fatty acids and a novel modulation mechanism on ASIC channels

BPS2025 - DHA differentially modulates ASIC3 through interactions with transmembrane residues

Molecular Insights into Single Chain Lipid Modulation of Acid-Sensing Ion Channel 3

EL20, a potent antiarrhythmic compound, selectively inhibits calmodulin-deficient ryanodine receptor type 2