Biochemical and Biophysical Research Communications
Mini reviewWill cardiac optogenetics find the way through the obscure angles of heart physiology?
Introduction
The discovery that the biological activity of a large class of cells relies on changes in the distribution of charges between the inner and outer side of the plasma membrane, regulating the so-called membrane potential, has led to the gross classification of cell types into excitable and non-excitable. Unsurprisingly, the functional study of physiology and pathophysiology of excitable cells, which notably include neurons and muscles, has made intense use of electricity, either applied locally to single cells in vitro (i.e. with a patch clamp pipette) or delivered to an intact organ (i.e. via extracellular electrodes). Whilst these approaches uncovered the fundamentals of excitable cell biology, they have been suffering from invasiveness and lack of selectivity, which limit their utility in the understanding of the function of specific cells in their complex physiologic environment, often including several interconnected excitable cell types. The most visionary scientists in the field, had “ … been interested for some time in potential methods by which mammalian neurons might be transfected with a gene whose product would permit light-triggering of depolarizations and action potentials … ” (RY Tsien, in Ref. [1]), in other words, they were seeking strategies for non-invasive control of excitable cell function. Once again, Nature itself brought us the solution, represented by ion-channels sensitive to light, whose function is at the basis of the phototaxic behavior of unicellular organisms, mostly algae [2]. Not many could envisage that such simple organisms would offer the instruments to uncover physiology of the most complicated mammalians, and above all, humans. These tools are represented by the class of proteins, collectively named opsins, which, combined to the progress in molecular biology, opened the revolutionary road of optogenetics.
Section snippets
Fundamentals of optogenetics
The prototypical opsin, and the most used so far, is Channelrhodopsin-2 (ChR2), a seven transmembrane domain light-gated cation channel, which undergoes a rapid conformational change upon illumination with light at a relatively narrow range of excitation wavelengths, around 470 nm. When ChR2 is expressed on cell membranes, absorption of blue light opens the channel, triggering an inward current, which results in membrane depolarization, rapidly reversible with the channel closure in the dark [3]
Optogenetics in cardiac physiology
The central nervous system has been the initial and preferred target of the in vivo optogenetic investigations in laboratory animals. This is due to the obvious interest in defining the neurobiological basis of brain function, with a method surpassing the intrinsic limitations of the existing experimental techniques. It is well appreciated that different neuron types establish specific interactions to generate complex neural circuits, which underlie the neuro-anatomical basis of brain function.
Tissue determinants of extrasystolic heart beats and arrhythmia triggers
Arrhythmias are complex phenomena, involving multiple myocardial cell types, with a wide variety of consequences ranging from benign palpitations, to contractile failure and sudden cardiac death. Arrhythmogenic conditions include both genetically-determined (e.g. Catecholaminergic Polymorphic Ventricular Tachycardia, Brugada syndrome, long QT syndrome, Arrhythmogenic CardioMyopathy) and acquired diseases (e.g. myocardial hypertrophy, ischemia, fibrosis). Although the specific arrhythmia
Research and development of new light sources
The use of light emission in cells, tissues, or intact animals has dominated experimental biology, over the last few decades, and this has brought to the wide offer of thoroughly tested molecular tools and instrumental devices which is now available. The explosion in the number of experiments using optogenetics in different, and often unexplored tissue contexts, in vivo, has similarly stimulated the rapidly evolving research of new suitable technologies. One of the most obvious technological
Therapeutic potential of cardiac optogenetics
At first glance, it may seem that the translational perspectives of cardiac optogenetics are far-fetched, since the unconditional requirement of this method is the expression of an algal-derived protein in men. However, recent development of safe and efficient gene delivery strategies, which counts several clinical trials approved by the FDA, brings closer the possible clinical application of optogenetics for disease therapy. The first example is represented by a recently approved clinical
Concluding remarks
Cardiac optogenetics has introduced itself to the world of neurosciences as a revolutionary and long sought-after method to modulate the function of specific neuronal circuits in living and conscious animals. The applications of such biotechnology for cardiac studies have lagged behind, while the appropriate tools, including both the animal models and experimental protocols were developed. We are now at the stage when a significant optogenetics toolkit is validated and available, and described
Sources of funding
The work was supported by Telethon Foundation, Grant n. GGP11224 to Marco Mongillo.
Conflict of interest
Nothing to declare.
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Optogenetics gets to the heart: A guiding light beyond defibrillation
2017, Progress in Biophysics and Molecular BiologyCitation Excerpt :First, several works have explored ways for non-transgenic expression of ChR2 in the heart, implying a potential use in the human heart too. As comprehensively reviewed by Entcheva's group (Ambrosi et al., 2014; Entcheva, 2013) and by others (Bruegmann and Sasse, 2015; Pianca et al., 2016), cell- and viral-mediated delivery are the two main options for inscribing light-sensitivity in the heart. The cell-mediated delivery is based on the engraftment of in-vitro-manipulated cells that express ChR2 and are capable of electrically coupling with cardiomyocytes (Jia et al., 2011).
Optogenetic Control of Heart Rhythm: Lightly Guiding the Cardiac Pace
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2021, Frontiers in PhysiologySteering Molecular Activity with Optogenetics: Recent Advances and Perspectives
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