PART I Cellular Physiology CHAPTER Homeostasis and Cellular Signaling Patricia J. Gallagher, Ph.D. 11 George A. Tanner, Ph.D. CHAPTER OUTLINE ■ THE BASIS OF PHYSIOLOGICAL REGULATION ■ SECOND MESSENGER SYSTEMS AND ■ MODES OF COMMUNICATION AND SIGNALING INTRACELLULAR SIGNALING PATHWAYS ■ THE MOLECULAR BASIS OF CELLULAR SIGNALING ■ INTRACELLULAR RECEPTORS AND HORMONE ■ SIGNAL TRANSDUCTION BY PLASMA MEMBRANE SIGNALING RECEPTORS KEY CONCEPTS 1. Physiology is the study of the functions of living organisms 7. Different modes of cell communication differ in terms of and how they are regulated and integrated. distance and speed. 2. A stable internal environment is necessary for normal cell 8. Chemical signaling molecules (first messengers) provide function and survival of the organism. the major means of intercellular communication; they in- 3. Homeostasis is the maintenance of steady states in the clude ions, gases, small peptides, protein hormones, body by coordinated physiological mechanisms. metabolites, and steroids. 4. Negative and positive feedback are used to modulate the 9. Receptors are the receivers and transmitters of signaling body’s responses to changes in the environment. molecules; they are located either on the plasma mem- 5. Steady state and equilibrium are distinct conditions. brane or within the cell. Steady state is a condition that does not change over time, 10. Second messengers are important for amplification of the while equilibrium represents a balance between opposing signal received by plasma membrane receptors. forces. 11. Steroid and thyroid hormone receptors are intracellular 6. Cellular communication is essential to integrate and coor- receptors that participate in the regulation of gene ex- dinate the systems of the body so they can participate in pression. different functions. hysiology is the study of processes and functions in living distribution of ions across cell membranes is described in ther- Porganisms. It is a broad field that encompasses many dis- modynamic terms, muscle contraction is analyzed in terms of ciplines and has strong roots in physics, chemistry, and math- forces and velocities, and regulation in the body is described ematics. Physiologists assume that the same chemical and in terms of control systems theory. Because the functions of physical laws that apply to the inanimate world govern living systems are carried out by their constituent structures, processes in the body. They attempt to describe functions in knowledge of structure from gross anatomy to the molecular chemical, physical, or engineering terms. For example, the level is germane to an understanding of physiology. 1 2 PART I CELLULAR PHYSIOLOGY The scope of physiology ranges from the activities or functions of individual molecules and cells to the interac- External environment tion of our bodies with the external world. In recent years, we have seen many advances in our understanding of phys- iological processes at the molecular and cellular levels. In Lungs higher organisms, changes in cell function always occur in Alimentary the context of a whole organism, and different tissues and tract organs obviously affect one another. The independent ac- Kidneys tivity of an organism requires the coordination of function at all levels, from molecular and cellular to the organism as a whole. An important part of physiology is understanding Internal how different parts of the body are controlled, how they in- environment teract, and how they adapt to changing conditions. For a person to remain healthy, physiological conditions in the body must be kept at optimal levels and closely reg- ulated. Regulation requires effective communication be- Body cells tween cells and tissues. This chapter discusses several top- ics related to regulation and communication: the internal environment, homeostasis of extracellular fluid, intracellu- Skin lar homeostasis, negative and positive feedback, feedfor- ward control, compartments, steady state and equilibrium, intercellular and intracellular communication, nervous and endocrine systems control, cell membrane transduction, and important signal transduction cascades. FIGURE 1.1 The living cells of our body, surrounded by an internal environment (extracellular fluid), communicate with the external world through this medium. Exchanges of matter and energy between the body and THE BASIS OF PHYSIOLOGICAL REGULATION the external environment (indicated by arrows) occur via the gas- trointestinal tract, kidneys, lungs, and skin (including the special- Our bodies are made up of incredibly complex and delicate ized sensory organs). materials, and we are constantly subjected to all kinds of disturbances, yet we keep going for a lifetime. It is clear that conditions and processes in the body must be closely maintain a relatively constant internal environment. A controlled and regulated, i.e., kept at appropriate values. good example is the ability of warm-blooded animals to live Below we consider, in broad terms, physiological regula- in different climates. Over a wide range of external temper- tion in the body. atures, core temperature in mammals is maintained con- stant by both physiological and behavioral mechanisms. This stability has a clear survival value. A Stable Internal Environment Is Essential for Normal Cell Function Homeostasis Is the Maintenance of The nineteenth-century French physiologist Claude Steady States in the Body by Bernard was the first to formulate the concept of the inter- Coordinated Physiological Mechanisms nal environment (milieu intérieur). He pointed out that an ex- ternal environment surrounds multicellular organisms (air The key to maintaining stability of the internal environ- or water), but the cells live in a liquid internal environment ment is the presence of regulatory mechanisms in the body. (extracellular fluid). Most body cells are not directly ex- In the first half of the twentieth century, the American posed to the external world but, rather, interact with it physiologist Walter B. Cannon introduced a concept de- through the internal environment, which is continuously scribing this capacity for self-regulation: homeostasis, the renewed by the circulating blood (Fig. 1.1). maintenance of steady states in the body by coordinated For optimal cell, tissue, and organ function in animals, physiological mechanisms. several conditions in the internal environment must be The concept of homeostasis is helpful in understanding maintained within narrow limits. These include but are not and analyzing conditions in the body. The existence of limited to (1) oxygen and carbon dioxide tensions, (2) con- steady conditions is evidence of regulatory mechanisms in centrations of glucose and other metabolites, (3) osmotic the body that maintain stability. To function optimally un- pressure, (4) concentrations of hydrogen, potassium, cal- der a variety of conditions, the body must sense departures cium, and magnesium ions, and (5) temperature. Depar- from normal and must engage mechanisms for restoring tures from optimal conditions may result in disordered conditions to normal. Departures from normal may be in the functions, disease, or death. direction of too little or too much, so mechanisms exist for Bernard stated that “stability of the internal environment opposing changes in either direction. For example, if blood is the primary condition for a free and independent exis- glucose concentration is too low, the hormone glucagon, tence.” He recognized that an animal’s independence from from alpha cells of the pancreas, and epinephrine, from the changing external conditions is related to its capacity to adrenal medulla, will increase it. If blood glucose concentra- CHAPTER 1 Homeostasis and Cellular Signaling 3 tion is too high, insulin from the beta cells of the pancreas water within cells. Cells can regulate their ionic strength by will lower it by enhancing the cellular uptake, storage, and maintaining the proper mixture of ions and un-ionized metabolism of glucose. Behavioral responses also contribute molecules (e.g., organic osmolytes, such as sorbitol). to the maintenance of homeostasis. For example, a low Many cells use calcium as an intracellular signal or “mes- blood glucose concentration stimulates feeding centers in senger” for enzyme activation, and, therefore, must possess the brain, driving the animal to seek food. mechanisms for regulating cytosolic [Ca2ϩ]. Such funda- Homeostatic regulation of a physiological variable often mental activities as muscle contraction, the secretion of involves several cooperating mechanisms activated at the neurotransmitters, hormones, and digestive enzymes, and same time or in succession. The more important a variable, the opening or closing of ion channels are mediated via the more numerous and complicated are the mechanisms transient changes in cytosolic [Ca2ϩ]. Cytosolic [Ca2ϩ] in that keep it at the desired value. Disease or death is often resting cells is low, about 10Ϫ7 M, and far below extracel- the result of dysfunction of homeostatic mechanisms. lular fluid [Ca2ϩ] (about 2.5 mM). Cytosolic [Ca2ϩ] is reg- The effectiveness of homeostatic mechanisms varies ulated by the binding of calcium to intracellular proteins, over a person’s lifetime. Some homeostatic mechanisms are transport is regulated by adenosine triphosphate (ATP)-de- not fully developed at the time of birth. For example, a pendent calcium pumps in mitochondria and other or- newborn infant cannot concentrate urine as well as an adult ganelles (e.g., sarcoplasmic