The Cardiac Pacemaker Story—Fundamental Role of the Na+/Ca2+ Exchanger in Spontaneous Automaticity

The electrophysiological mechanism of the sinus node automaticity was previously considered exclusively regulated by the so-called “funny current”. However, parallel investigations increasingly emphasized the importance of the Ca$^{2+}$-homeostasis and Na+/ Ca$^{2+}$ exchanger (NCX). Recently, increasing experimental evidence, as well as insight through mechanistic in silico modeling demonstrates the crucial role of the exchanger in sinus node pacemaking. NCX had a key role in the exciting story of discovery of sinus node pacemaking mechanisms, which recently settled with a consensus on the coupled-clock mechanism after decades of debate. This review focuses on the role of the Na$^{+}$/Ca$^{2+}$ exchanger from the early results and concepts to recent advances and attempts to give a balanced summary of the characteristics of the local, spontaneous, and rhythmic Ca$^{2+}$ releases, the molecular control of the NCX and its role in the fight-or-flight response. Transgenic animal models and pharmacological manipulation of intracellular Ca$^{2+}$ concentration and/or NCX demonstrate the pivotal function of the exchanger in sinus node automaticity. We also highlight where specific hypotheses regarding NCX function have been derived from computational modeling and require experimental validation. Nonselectivity of NCX inhibitors and the complex interplay of processes involved in Ca$^{2+}$ handling render the design and interpretation of these experiments challenging

Prenatal exposures and exposomics of asthma

This review examines the causal investigation of preclinical development of childhood asthma using exposomic tools. We examine the current state of knowledge regarding early-life exposure to non-biogenic indoor air pollution and the developmental modulation of the immune system. We examine how metabolomics technologies could aid not only in the biomarker identification of a particular asthma phenotype, but also the mechanisms underlying the immunopathologic process. Within such a framework, we propose alternate components of exposomic investigation of asthma in which, the exposome represents a reiterative investigative process of targeted biomarker identification, validation through computational systems biology and physical sampling of environmental medi

Intracellular Calcium and Ischemic Damage: Dual Role of the Na+/Ca2+ Exchanger

Introduction The book describes the significant multidisciplinary research findings at the Università Politecnica delle Marche and the expected future advances. It addresses some of the most dramatic challenges posed by today’s fast-growing, global society and the changes it has caused. It also discusses solutions to improve the wellbeing of human beings. The book covers the main research achievements in the various disciplines of the life sciences, and includes chapters that highlight mechanisms relevant to all aspects of human diseases, the molecular, cellular, and functional basis of therapy, and its translation into the management of people’s health needs. It also describes research on traditional and innovative foods to enhance quality, safety and functionality, and to develop bioactive/nutraceutical compounds. Further chapters address conservation and management of various environments, from the forests to the oceans, describing the studies on countermeasures against climate changes and terrestrial/aquatic pollutants, and on terrestrial/marine biodiversity, ecosystems and landscapes, erosion of genetic biodiversity, innovative aquaculture feed, sustainable crop production and management of forests. Lastly, the book reports the findings of research work on different classes of biomolecules, and on the molecular basis of antibiotic resistances and their diffusion

A new role of AMP-activated protein kinase in regulating proliferation of mesenchymal stem cells

Purpose: Natriuretic peptides (NPs) administered during early reperfusion are protective in models of myocardial infarction. A previous study examining the endogenous components of B-type natriuretic peptide (BNP) protection of reperfused myocardium, implicated both sarcolemmal (s) KATP and mitochondrial (m) KATP channels. The indirect evidence characterising the relationship between BNP signalling and KATP was obtained using sulphonylurea receptor inhibitors in a rat isolated heart model of ischaemia-reperfusion injury. Here we seek to further examine the relationship between NPs and sKATP openings using single channel electrophysiology. Given our previous findings and the overarching consensus that cardioprotective autacoids open KATP channels, it was hypothesised that NPs elicit sKATP opening. Methods: Cardiomyocyte isolation. Left ventricular cardiomyocytes were isolated from male Sprague-Dawley rat hearts subjected to enzymatic digestion with Liberase Blendzyme DL. Cardiomyocytes were cultured overnight in Medium 199, prior to patch clamp. Single channel patch clamp. Single channel recordings at room temperature (22°C) were made from cell attached patches bathed in Na+ Locke, pH 7.2. The recording pipette contained high KCl (140 mM), pH 7.2. Recordings (45 sec) were made over a range of patch potentials (0, -30, -60, -90, -120 mV), in the absence (control) and in the presence of bath applied BNP (10, 100 nM and 1 µM), pinacidil (200 µM) or pinacidil vehicle (DMSO, 0.25%). Recordings were also made with BNP and pinacidil applied concomitantly. Data are mean ± S.E.M. Results: The current voltage relationship of sKATP under control conditions was linear at –ve patch potentials, the mean conductance being 52.9 ± 1.8 pS (n = 18 hearts, n = 35 cells). Pinacidil caused a four fold increase in sKATP open probability compared to control. Mean channel conductance in the presence of pinacidil was 59.9 ± 1.9 pS (n = 16 hearts, n = 44 cells). Interestingly BNP at all concentrations had negligible effects on sKATP open probability and unitary conductance. However, BNP at all concentrations and patch potentials inhibited pinacidil induced sKATP openings, restoring channel open probability to baseline. Conclusion: These data illustrate the inhibitory effect of NP signalling on sKATP function in the cardiomyocyte under normoxia. They are concordant with the inhibitory effect of atrial NP on KATP in the pancreatic beta cell, but are in apparent conflict with the current cardioprotection paradigm. However, differential effects on sKATP and mKATP and the effects of hypoxia-reoxygenation require further exploration