Signal Transduction Pathways

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I. Binding a chemical messenger activates a receptor, and this initiates one or more signal transduction pathways leading to the cell's response.

II. 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 or secretion of the proteins coded by the genes.

III. 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.

Vander et al.: Human Physiology: The Mechanism of Body Function, Eighth Edition

Homeostatic Mechanisms and Cellular Communication CHAPTER SEVEN

a. 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.

b. The receptor may itself act as an enzyme. With one exception, the enzyme activity is that of a protein kinase, usually a tyrosine kinase. The exception is the receptor that functions as a guanylyl cyclase to generate cyclic GMP.

c. The receptor may activate a cytosolic JAK kinase associated with it.

d. The receptor may interact with an associated plasma-membrane G protein, which in turn interacts with plasma-membrane effector proteins—ion channels or enzymes.

e. Very commonly, the receptor may activate, via a Gs protein, or inhibit, via a Gi 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.

f. The receptor may activate, via a G protein, the plasma-membrane enzyme phospholipase C, which catalyzes the formation of diacylglycerol (DAG) and inositol trisphosphate (IP3). DAG activates protein kinase C, and IP3 acts as a second messenger to release calcium from the endoplasmic reticulum.

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. The calcium ion is one of the most widespread second messengers.

a. An activated receptor can increase cytosolic calcium concentration by causing certain calcium channels in the plasma membrane and/or endoplasmic reticulum to open. Voltage-gated calcium channels can also influence cytosolic calcium concentration.

b. Calcium binds to one of several intracellular proteins, most often calmodulin. Calcium-activated calmodulin activates or inhibits many proteins, including calmodulin-dependent protein kinases.

VI. 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 code for still other transcription factors. This is particularly true in pathways initiated by first messengers that stimulate their target cell's proliferation or differentiation. VII. Cessation of receptor activity occurs by decreased first messenger molecule concentration and when the receptor is chemically altered or internalized, in the case of plasma-membrane receptors.

SECTION B KEY TERMS

receptor (for messengers)

specificity saturation competition antagonist agonist down-regulation up-regulation receptor activation signal transduction pathway transcription factor first messenger second messenger protein kinase tyrosine kinase guanylyl cyclase cyclic GMP (cGMP) cGMP-dependent protein kinase

JAK kinase G protein plasma-membrane effector protein adenylyl cyclase cyclic AMP (cAMP) phosphodiesterase cAMP-dependent protein kinase phospholipase C diacylglycerol (DAG) inositol trisphosphate (IP3) protein kinase C calmodulin calmodulin-dependent protein kinase primary response genes (PRGs)

SECTION B REVIEW QUESTIONS

What is the chemical nature of receptors? Where are they located?

Explain why different types of cells may respond differently to the same chemical messenger. Describe how the metabolism of receptors can lead to down-regulation or up-regulation. What is the first step in the action of a messenger on a cell?

Describe the signal transduction pathway used by lipid-soluble messengers.

Classify plasma-membrane receptors according to the signal transduction pathways they initiate. What is the result of opening a membrane ion channel?

Contrast receptors that have intrinsic enzyme activity with those associated with cytoplasmic JAK kinases.

Describe the role of plasma-membrane G proteins. Draw a diagram describing the adenylyl cyclase-cAMP system.

Draw a diagram illustrating the phospholipase C/DAG/IP3 system.

Contrast direct and indirect gating of ion channels by G proteins.

What are the two general mechanisms by which first messengers elicit an increase in cytosolic calcium concentration? What are the sources of the calcium in each mechanism?

How does the calcium-calmodulin system function? Describe the manner in which activated plasmamembrane receptors influence gene expression.

PART TWO Biological Control Systems

Vander et al.: Human Physiology: The Mechanism of Body Function, Eighth Edition

PART TWO Biological Control Systems

CHAPTER 7 CLINICAL TERMS

aspirin nonsteroidal antiinflammatory drugs (NSAIDs)

adrenal steroids jet lag heart attack asthma

Werner's syndrome hypertension myasthenia gravis

CHAPTER 7 THOUGHT QUESTIONS

(Answers are given in Appendix A.)

1. A person's plasma potassium concentration (a homeostatically regulated variable) is 4mmol/L when she is eating 150 mmol of potassium per day. One day she doubles her potassium intake and continues to eat that amount indefinitely. At the new steady state, do you think her plasma potassium concentration is more likely to be 8, 4.4, or 4mmol/L? (The answer to this question requires no knowledge about potassium, only the ability to reason about homeostatic control systems.)

2. Eskimos have a remarkable ability to work in the cold without gloves and not suffer decreased skin blood flow. Does this prove that there is a genetic difference between Eskimos and other people with regard to this characteristic?

3. Patient A is given a drug that blocks the synthesis of all eicosanoids, whereas patient B is given a drug that blocks the synthesis of leukotrienes but none of the other eicosanoids. What are the enzymes most likely blocked by these drugs?

4. Certain nerves to the heart release the neurotransmitter norepinephrine. If these nerves are removed in experimental animals, the heart becomes extremely sensitive to the administration of a drug that is an agonist of norepinephrine. Explain why, in terms of receptor physiology.

5. A particular hormone is known to elicit, completely by way of the cyclic AMP system, six different responses in its target cell. A drug is found that eliminates one of these responses but not the other five. Which of the following, if any, could the drug be blocking: the hormone's receptors, Gs protein, adenylyl cyclase, or cyclic AMP?

6. If a drug were found that blocked all calcium channels directly linked to G proteins, would this eliminate the role of calcium as a second messenger?

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Essentials of Human Physiology

Essentials of Human Physiology

This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.

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Responses

  • Grimalda
    Which of these is not correct phospholipase c catalyzes the formation of ip3.?
    8 years ago
  • Matilde
    What are signal pathways in physiology?
    7 years ago
  • Aida
    What is the signal transduction pathway that lipid soluble messenger use?
    7 years ago
  • Robinia
    What is the function of the second messenger in signal transduction pathway?
    7 years ago
  • Adonay Demsas
    Why different types of cells may respond differently to the same chemical messenger.?
    7 years ago
  • ulla-maj
    What is lipidsoluble cells signals i?
    2 months ago

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