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

PDXScholar Dissertations and Theses Dissertations and Theses Let us know how access to this document benefits you. Abstract The cardiac ryanodine receptor (RyR2) is a Ca 2+ ion channel found in the sarcoplasmic reticulum (SR), an intracellular membranous Ca 2+ storage system. It is well known that a destabilization of RyR2 can lead to a Ca 2+ flux out of the SR, which results in an overload of intracellular Ca 2+ ; this can also lead to arrhythmias and heart failure. The catecholamines play a large role in the regulation of RyR2; stimulation of the β-adrenergic receptor on the cell membrane can lead to a hyperphosphorylation of RyR2, making it more leaky to Ca 2+. We have previously shown that strong electron donors will inhibit RyR2. It is hypothesized that the catecholamines, sharing a similar structure with other proven inhibitors of RyR2, will also inhibit RyR2. Here we confirm this hypothesis and show for the first time that the catecholamines, isoproterenol and epinephrine, act as strong electron donors and inhibit RyR2 activity at the single channel level. This data suggests that the catecholamines can influence RyR2 activity at two levels. This offers promising insight into the potential development of a new class of drugs to treat heart failure and arrhythmia; ones that can both prevent the hyperphosphorylation of RyR2 by blocking the β-adrenergic receptor, but can also directly inhibit the release of Ca 2+ from RyR2. ii Dedication This thesis is dedicated to my family, who have loved and supported me through my life in both the good and the bad. If it wasn't for them I would not be where I am today.

/pdf/catecholamime-interactions-with-the-cardiac-ryanodine-4ugpsxcehk.pdf

Catecholamime Interactions with the Cardiac Ryanodine Receptor

Novel Compounds Inhibit Calmodulin Deficient RyR2 Activity and Arrhythmias in a CPVT Mouse Model

Stomatin is a monotopic integral membrane protein found in all classes of life that has been shown to regulate members of the Acid-Sensing Ion Channel (ASIC) family. However, the mechanism by which Stomatin alters ASIC function is not known. Using chimeric channels, we combined patch clamp electrophysiology and FRET to search for regions of ASIC3 critical for binding to and regulation by Stomatin. With this approach, we found that regulation requires two distinct sites on ASIC3: the distal C-terminus and the first transmembrane domain. Mutation of the C-terminal site disrupts binding and regulation whereas disruption of the transmembrane site eliminates functional regulation. We then showed that Stomatin does not alter surface expression using fluorescence imaging and a surface biotinylation assay. Based on these findings, we propose a model whereby STOM is anchored to the channel via a site on the distal C-terminus but alters ASIC3 gating through action on TM1.

https://biorxiv.org/content/biorxiv/early/2019/07/16/704064.full-text.pdf

Insights into the molecular mechanisms underlying the inhibition of acid-sensing ion channel 3 gating by Stomatin

Inflammatory mediators including polyunsaturated fatty acids (PUFAs) are known to potentiate ASIC3 by inducing changes in multiple gating features, yet the molecular basis for their interactions remains poorly defined. Using all-atom MD simulations and electrophysiology, we show that DHA accumulates around ASIC3 through loosely coordinated interactions with a membrane-facing electropositive region along the outer leaflet of TM1. In the open state, the carboxylate head group strongly binds to a critical arginine (R63) along with nearby polar residues that are necessary to slow the rate in channel desensitization rate but not to increase the pH sensitivity for channel activation. Moreover, mutating R63 disrupted effects on ASIC3 desensitization induced by PUFAs but not N-acyl amino acids (NAAAs) or lysophosphatidylcholines (LPCs). Our results provide the first detailed description of a functional PUFA binding site on ASICs, offering new insights into lipid modulation and potential strategies for developing novel therapeutics for pain and inflammation.

PUFA modulation of ASIC3 involves both specific and lipid solvent-like interactions

............................................................................................................................... i Dedication ............................................................................................................................ii Acknowledgements ............................................................................................................. iii List of Tables ...................................................................................................................... vii List of Figures .................................................................................................................... viii

/pdf/novel-compound-84f2-inhibits-calmodulin-deficient-ryr2-3liyiat1uj.pdf

Novel Compound, 84F2, Inhibits Calmodulin Deficient RyR2

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