Cellular Signal Transduction in Toxicology and Pharmacology

Data Collection, Analysis, and Interpretation

Jonathan W. Boyd, Richard R. Neubig, Jonathan W. Boyd, Richard R. Neubig

• Publisher: Wiley
• Year: 2019
• Print ISBN: 9781119060260
• eBook ISBN: 9781119060161
• Edition: 1
• Topic: Physical Sciences
• Subtopic: Biochemistry

Covering a key topic due to growing research into the role of signaling mechanisms in toxicology, this book focuses on practical approaches for informatics, big data, and complex data sets.

• Combines fundamentals / basics with experimental applications that can help those involved in preclinical drug studies and translational research
• Includes detailed presentations of study methodology and data collection, analysis, and interpretation
• Discusses tools like experimental design, sample handling, analytical measurement techniques

1
Introduction to Cellular Signal Transduction: The Connection Between a Biological System and Its Surroundings

Jonathan W. Boyd¹, Richard R. Neubig², Alice Han³, and Maren Prediger⁴

¹ Department of Orthopaedics and Department of Physiology and Pharmacology, West Virginia University School of Medicine, Morgantown, WV, USA

² Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA

³ Chem Bio & Exposure Sci Team, Pacific Northwest National Laboratory, Richland, WA, USA

⁴ Institute for Microproductions, Leibniz University, Hannover, Germany

The rate of energy flow governs anabolic processes in chemical and biological systems. When a steady flow of external energy enters into an open system, there is a driving force to assemble mechanisms from available components in order to disperse more energy in the quest for a stationary steady state [1]. The driving force does not distinguish between mechanisms of energy transduction but favors those that disperse energy more efficiently. The mechanisms that effectively distribute energy become temporal repositories of that energy, which allows other mechanisms (i.e. energy dispersal systems) to tap into them, which further enhances energy dispersal and ultimately creates networks (Figure 1.1).

Figure 1.1 Schematic displaying energy dispersion.

A commonplace example of this classic thermodynamic phenomenon is a hot cup of coffee reaching equilibrium with a cooler room temperature; convection waves – in addition to thermal radiation – allow the fastest distribution of energy to the local environment. In regard to ecology, times of plenty can yield massive population increases eager to consume (i.e. distribute) as much energy as possible; finally, in relevance to cellular signal transduction, many distribution networks are directly linked to energy availability via direct interaction with adenosine triphosphate (ATP). It is important to note, however, that the availability of energy on Earth is not at steady state (e.g. seasons of the year) and, in fact, is kept far from equilibrium [2]. Therefore, given an environmental change, where the rate of energy delivery changes dramatically, self‐assembly processes must adapt to the new steady‐state or risk infinite dissolution, via increasing entropy. Biological systems have the advantage here and are able to re‐create themselves individually through mutation or reposition themselves within a group or network for optimization in this new environment.

The means by which biological systems sense, interpret, and respond to new information from a dynamic external environment involve signal transduction. Signal transduction can be simply defined as the transformation of information from one form into an alternative form, often leading to a measurable action. While this is a very broad definition that fosters a conceptual understanding of signaling in general, it encompasses whole‐organism response, including sensory perception. For example, the ability to transform a signal from a sudden change in air pressure (e.g. from a loud GROWL in the forest) into an action (e.g. “RUN!”) is a process that involves multiple cell types with highly integrated signal transduction networks; in this example, cells deep within the inner ear polarize or depolarize in response to sound waves and detect the stimuli based on the magnitude and direction of hair movement. Cellular signal transduction has a much narrower scope and can be defined as a basic process that involves the conversion of a signal from outside the cell to a functional change within the cell. However, it is important to remember that the response of multicellular biological organisms necessarily involves the coordinated efforts of many cells and that cells can and do signal to each other (even though they may be spatially separated). Therefore, while this book is focused on cellular signal transduction in pharmacology and toxicology, the signaling responses discussed herein are often the foundation of both human diseases and treatment options.

Understanding the potential biological ramifications associated with altered cellular signal transduction processes is essential for research, development, testing, and evaluation of new chemical compounds for both pharmacology and toxicology. From a pharmaceutical viewpoint, the number of signal transduction proteins that are druggable targets is continuing to grow (see Santos et al. [3] for review), while toxicological sciences are beginning to appreciate the multitude of compounds that impact signaling cascades and how these impacts can/do lead to adverse health effects (see Toxicity Testing in the 21st Century[4]). Given the highly integrated nature of most signal transduction networks, elucidating either the pharmacologic or toxicologic activity of new compounds can be difficult when there are no available standard operating procedures for testing their influence on signaling cascades. Challenges for scientists moving forward are as follows: (i) how to understand the relationship between seemingly disparate signaling networks (e.g. pro‐survival and pro‐death), (ii) determining the impacts that dose has on signaling (e.g. defining biological thresholds), and (iii) defining the temporal scale associated with response (e.g. implications of acute vs. chronic exposures), among many others. Beyond initiating discussions that we hope will facilitate research that fills exiting knowledge gaps, we hope that this book will inform the reader of currently available tools and techniques that enable them to begin to clarify the critical role that cellular signal transduction plays in the biological response to any industry‐relevant compounds.

1.1 Starting Big, but Ending Small

While the definition of what constitutes life may be difficult and hotly debated [5–7], it can be defined as “the property or quality that distinguishes living organisms from dead organisms and inanimate matter, manifested in functions such as metabolism, growth, reproduction, and response to stimuli or adaptation to the environment originating from within the organism” [8]. From this framework, one can easily see the central role that cellular signal transduction plays in maintaining “life.” Every one of the listed functions, which are all clearly associated with the existence of life, is firmly linked to the foundation of cellular signal transduction or the ability of cells (using a cell as the fundamental unit of life) to transform signals from one form into another toward functional outcomes such as growth and reproduction. Beyond simply sensing the environment, cellular signal transduction drives the processes of life by ini...

Table of contents

• Cover
• Table of Contents
• List of Contributors
• About the Editors
• Preface
• 1 Introduction to Cellular Signal Transduction
• 2 Mechanisms of Cellular Signal Transduction
• 3 From Cellular Mechanisms to Physiological Responses
• 4 Signal Transduction in Disease
• 5 Experimental Design in Signal Transduction
• 6 Techniques for Measuring Cellular Signal Transduction
• 7 Computational Methods for Signal Transduction
• 8 A Toxicological Application of Signal Transduction
• 9 Future Research in Signaling
• Index
• End User License Agreement