Calcium In Muscle Activation

This book offers a comparative and interdisciplinary approach to excitation-contraction-coupling in smooth and striated mus cles, including the myocardium. It is an account of the path ways and mechanisms by which cellular calcium is handled and activates the contractile proteins. It also describes how these mechanisms are adapted in various kinds of muscle to meet specific functional requirements, such as speed or economy. This monograph then presents facts, ideas and theories and the evidence on which they are based, and ifit stimulates others and furthers research, it will have served its purpose. All of the chapters are self-contained and may be read in any order, but readers unfamiliar with muscle are recommended to start with the introductory chapter on excitation and contraction. During all the years of writing this book, I received enormous help from Isolde Berger who corrected, edited and transformed my innumerable notes and drafts into a readable manuscript; she also compiled the list of references and the Subject Index. I owe a great debt of gratitude to her and also to Claudia Zeugner, who prepared the figures with expertise and care. Then I would like to thank the Deutsche F orschungs gemeinschaft and the Fritz-Thyssen-Stiftung for supporting the work of my Department which has been reported in this monograph. A great many people contributed with helpful discussions.

Recent years have witnessed an explosion of knowledge lea- ding to a molecular understanding of the mechanisms of ac- tion of calcium on excitation and contraction coupling and its role in the regulation of contractility. This book highlights the most recent progress as well as providing a historial perspective of the field. It presents a concise and comprehensive overview of our current knowledge regar- ding calcium channels and regulatory proteins as well as in- tracellular calcium handling and the mechanisms underlying the activation of contractile proteins. It also describes how these basic mechanisms have been adapted in various types of muscle, especially in cardiac and smooth muscle.

Understanding the molecular mechanism of muscle contraction started with the discovery that striated muscle is composed of interdigitating filaments which slide against each other. Sliding filaments and the working-stroke mechanism provide the framework for individual myosin motors to act in parallel, generating tension and loaded shortening with an efficient use of chemical energy. Our knowledge of this exquisitely structured molecular machine has exploded in the last four decades, thanks to a bewildering array of techniques for studying intact muscle, muscle fibres, myofibrils and single myosin molecules. After reviewing the mechanical and biochemical background, this monograph shows how old and new experimental discoveries can be modelled, interpreted and incorporated into a coherent mathematical theory of contractility at the molecular level. The theory is applied to steady-state and transient phenomena in muscle fibres, wing-beat oscillations in insect flight muscle, motility assays and single-molecule experiments with optical trapping. Such a synthesis addresses major issues, most notably whether a single myosin motor is driven by a working stroke or a ratchet mechanism, how the working stroke is coupled to phosphate release, and whether one cycle of attachment is driven by the hydrolysis of one molecule of ATP. Ways in which the theory can be extended are explored in appendices. A separate theory is required for the cooperative regulation of muscle by calcium via tropomyosin and troponin on actin filaments. The book reviews the evolution of models for actin-based regulation, culminating in a model motivated by cryo-EM studies where tropomyosin protomers are linked to form a continuous flexible chain. It also explores muscle behaviour as a function of calcium level, including emergent phenomena such as spontaneous oscillatory contractions and direct myosin regulation by its regulatory light chains. Contraction models can be extended to all levels of calcium-activation by embedding them in a cooperative theory of thin-filament regulation, and a method for achieving this grand synthesis is proposed. Dr. David Aitchison Smith is a theoretical physicist with thirty years of research experience in modelling muscle contractility, in collaboration with experimental groups in different laboratories.

The Third International Symposium on Excitation-Contraction Coupling in Skeletal, Cardiac, and Smooth Muscle, organized by George Frank, C. Paul Bianchi, and Henk E. DJ. ter Keurs, was held in Banff Centre, Banff, Alberta, Canada during June 26 to June 30, 1991. The theme of these symposia has been to recognize the similarities and dissimilarities of excitation-contraction coupling in skeletal, cardiac, and smooth muscle. Cross fertilization of concepts of excitation-contraction coupling in these three types of muscle has occurred since the early studies in the late fifties and early sixties on skeletal muscle. Investigators in each field meet only at specialized symposia which exclude investigators in the other fields. The purpose of the symposia has been to bring together international investigators studying excitation-contraction coupling in skeletal, cardiac, and smooth muscle so that we may learn from each other and hence provide a more global concept of excitation-contraction. The Third International Symposia has accomplished its objective as we recognize that calcium channels of the sarcolemma and the sarcoplasmic reticulum play key essential roles in excitation-contraction coupling in all three types of muscles. In skeletal muscle the recognition that E-C coupling consists of two parallel mechanisms, one dependent upon a dihydropyridine voltage-sensitive sensors coupled to calcium release from the terminal cisternae via the ryanodine sensitive channel in the foot structure of the triad.

The endothelium, a monolayer of endothelial cells, constitutes the inner cellular lining of the blood vessels (arteries, veins and capillaries) and the lymphatic system, and therefore is in direct contact with the blood/lymph and the circulating cells. The endothelium is a major player in the control of blood fluidity, platelet aggregation and vascular tone, a major actor in the regulation of immunology, inflammation and angiogenesis, and an important metabolizing and an endocrine organ. Endothelial cells controls vascular tone, and thereby blood flow, by synthesizing and releasing relaxing and contracting factors such as nitric oxide, metabolites of arachidonic acid via the cyclooxygenases, lipoxygenases and cytochrome P450 pathways, various peptides (endothelin, urotensin, CNP, adrenomedullin, etc.), adenosine, purines, reactive oxygen species and so on. Additionally, endothelial ectoenzymes are required steps in the generation of vasoactive hormones such as angiotensin II. An endothelial dysfunction linked to an imbalance in the synthesis and/or the release of these various endothelial factors may explain the initiation of cardiovascular pathologies (from hypertension to atherosclerosis) or their development and perpetuation. Table of Contents: Introduction / Multiple Functions of the Endothelial Cells / Calcium Signaling in Vascular Cells and Cell-to-Cell Communications / Endothelium-Dependent Regulation of Vascular Tone / Conclusion / References

This is a collection of papers that presents a novel interpretation of data from the literature to reason logically for an overlooked mechanism of stimulus-contraction coupling in muscle. This mechanism is then used to explain aspects of the puzzles relating to both an important physiological function of the heart, The Frank-Starling Law, and the basis of a common inherited disease state, familial hypertrophic cardiomyopathy (FHCM).