SECTION A: HOMEOSTATIC CONTROL SYSTEMS

1. GENERAL CHARACTERISTICS OF HOMEOSTATIC CONTROL SYSTEMS
   1. Homeostasis denotes the stable conditions of the internal environment that result from the operation of compensatory homeostatic control systems.
      1. In a negative-feedback control system, a change in the variable being regulated brings about responses that tend to push the variable in the direction opposite to the original change. Negative feedback minimizes changes from the operating point of the system, leading to stability.
      2. In a positive-feedback system, an initial disturbance in the system sets off a train of events that increases the disturbance even further.
      3. Homeostatic control systems minimize changes in the internal environment but cannot maintain complete constancy because error signals drive the system.
      4. Feedforward regulation anticipates changes in a regulated variable, improves the speed of the body's homeostatic responses, and minimizes fluctuations in the level of the variable being regulated.

2. COMPONENTS OF HOMEOSTATIC CONTROL SYSTEMS
   1. The components of a reflex arc are receptor, afferent pathway, integrating center, efferent pathway, and effector. The pathways may be neural or hormonal.
   2. Local homeostatic responses are also stimulus-response sequences, but they occur only in the area of the stimulus, neither nerves nor hormones being involved.
   3. Intercellular communication is essential to reflexes and local responses and is achieved by neurotransmitters, hormones, and paracrine agents. Less common is intercellular communication through either gap junctions or cell-bound messengers.
   4. The eicosanoids are a widespread family of messenger molecules derived from arachidonic acid. They function mainly as paracrine and autocrine agents in local response.
      1. The first step in production of the eicosanoids is the splitting off of arachidonic acid from plasma membrane phospholipids by the action of phospholipase A.
      2. There are two pathways from arachidonic acid, one mediated by cyclooxygenase and leading to the formation of prostaglandins and thromboxanes, and the other mediated by lipoxygenase and leading to the formation of leukotrienes.

3. PROCESSES RELATED TO HOMEOSTASIS
   1. Acclimatization is an improved ability to respond to an environmental stress.
      1. The improvement is induced by prolonged exposure to the stress with no change in genetic endowment.
      2. If acclimatization occurs early in life, it may be irreversible and is known as a developmental acclimatization.

   2. Biological rhythms provide a feed forward component to homeostatic control systems.
      1. The rhythms are internally driven by brain pacemakers, but are entrained by environmental cues, such as light, which also serve to phase-shift (reset) the rhythms when necessary.
      2. In the absence of cues, rhythms free-run.

   3. Apoptosis (regulated cell death) plays an important role in homeostasis by helping to regulate cell numbers and eliminating undesirable cells.
   4. Aging is associated with a decrease in the number of cells in the body and with a disordered functioning of many of the cells that remain.
      1. It is a process distinct from the diseases associated with aging.
      2. Its physiological manifestations are a deterioration in organ-system function and in the capacity to respond homeostatically to environmental stresses.

   5. The balance of substances in the body is achieved by a matching of inputs and outputs. Total body balance of a substance may be negative, positive, or stable.

SECTION B: MECHANISMS BY WHICH CHEMICAL MESSENGERS CONTROL CELLS

1. RECEPTORS
   1. Receptors for chemical messengers are proteins located either inside the cell or, much more commonly, in the plasma membrane. The binding of a messenger by a receptor manifests specificity, saturation, and competition.
   2. Receptors are subject to physiological regulation by their own messengers. This includes down-regulation and up-regulation.

2. SIGNAL TRANSDUCTION PATHWAYS
   1. Binding a chemical messenger activates a receptor, and this initiates one or more signal transduction pathways leading to the cell's response.
   2. Lipid-soluble messengers bind to receptors inside the target cell, and the activated receptor acts in the nucleus as a transcription factor to alter the rate of transcription of specific genes, resulting in a change in the concentration of the protein in the cell or its rate of secretion from the cell.
   3. Lipid-insoluble messengers bind to receptors on the plasma membrane. The pathways induced by activation of the receptor often involve second messengers and protein kinases.
      1. The receptor may contain an ion channel, which opens, resulting in an electric signal in the membrane and, when calcium channels are involved, an increase in the cytosolic calcium concentration.
      2. The receptor may itself act as an enzyme. The most common enzyme activity is that of a protein kinase, specifically a tyrosine kinase.
      3. The receptor may interact with an associated plasma-membrane G protein, which in turn interacts with plasma-membrane effector proteins (ion channels or enzymes).
      4. Very commonly, the receptor may activate, via a G protein, or inhibit, via a G protein, the membrane effector enzyme adenylyl cyclase, which catalyzes the conversion of cytosolic ATP to cyclic AMP. Cyclic AMP acts as a second messenger to activate intracellular cAMP-dependent protein kinase, which phosphorylates proteins that mediate the cell's ultimate responses to the first messenger.

   4. The receptor, via a G protein, may directly open or close an adjacent ion channel. This differs from indirect G-protein gating of channels, in which a second messenger acts upon the channel.
   5. The calcium ion is one of the most widespread second messengers.
      1. An activated receptor can increase cytosolic calcium concentration by causing certain calcium channels in the plasma membrane and/or endoplasmic reticulum to open. In addition, voltage-gated calcium channels can influence cytosolic calcium concentration.
      2. Calcium binds to one of several intracellular proteins, most often calmodulin. Calcium-activated calmodulin activates or inhibits many proteins, including calmodulin-dependent protein kinases.

   6. The signal transduction pathways triggered by activated plasma-membrane receptors may influence genetic expression by activating transcription factors. In some cases the primary response genes influenced by these transcription factors encode still other transcription factors. This is particularly true in pathways initiated by first messengers that stimulate their target cell's proliferation or differentiation.
   7. Cessation of receptor activity occurs when the receptor is chemically altered or internalized, as in the case of plasma membrane proteins.