CHAPTER 11 Cell Signaling by Chemical Messengers OBJECTIVES: 1. Beginning with the release of a chemical messenger in response to a stimulus, list the common characteristics of all chemical messenger systems. 2. What is a signal transduction pathway? Name two types of targets of signal transduction pathways. 3. Beginning with the response to a stimulus, list the common characteristics of all chemical messenger systems as they apply to the chemical messenger acetylcholine at the neuromuscular junction. Use the terms nerve cell action potential, Ca2+-channel, vesicles, fusion, presynaptic membrane, acetylcholine, diffusion, acetylcholine receptors, gated ion channels, muscle cell action potential, and acetylcholinesterase. 4. Be able to determine when a chemical messenger is acting as an endocrine, paracrine, or autocrine substance. 5. What is a major difference between chemical messengers that are specific for intracellular receptors and those that are specific for plasma membrane receptors? 6. Describe the path taken by cortisol from the time it is released from the adrenal cortex until the time it affects gene transcription. Include serum albumin, steroid hormone binding globulin (SHBG), cortisol receptor, conformation change, nuclear translocation signal, dimerization, glucocorticoid response element (GRE), and regulation of gene transcription. 7. Concerning plasma membrane receptors for chemical messengers, how is the signal transduced? What are the two major effects upon the cell that result from chemical messenger binding? 8. What are signal transducer proteins? 9. When a protein contains a src homology 2 domain (SH2 domain), what does it bind to? Is the binding specific? 10. In the Ras and MAP kinase pathway, how does the occupied receptor activate Grb2? What is the last step in the pathway that is catalyzed by MAP-kinase and what is the effect? 11. What are the functions served by phosphatidylinositol phosphates in signal transduction? 12. What are the substrates and products of the reaction catalyzed by phospholipase C? 13. What are the substrates and products of the reaction catalyzed by phosphatidylinositol 3’ kinase? 14. What is the function of a pleckstrin homology domain? 15. What is the effect of insulin on protein synthesis and on glucose uptake and glycogen synthesis in muscle cells? Does this help to explain muscle wasting and hyperglycemia in a diabetic? 16. Be able to draw a cartoon of the insulin receptor that shows the cell membrane, two alpha-beta subunits, the membrane spanning region of the dimers, the insulin-binding site, the sites of tyrosine kinase domains, and the sites of auto-phosphorylation. Draw two IRS proteins bound to the receptor and indicate some of the sites phosphorylated on the IRS by the insulin receptor tyrosine kinases. Why do proteins bind to the phosphorylated IRS sites? 17. In the insulin signal transduction pathway that begins with the activation of phosphatidylinositol 3' kinase, name the down stream active kinase that dissociates from the membrane. Is this kinase a tyrosine or a serine/threonine kinase? 18. In the insulin signal transduction pathway that leads to the activation of MAP kinase, what is the signal transducer protein that binds to the IRS? Why does it bind to the IRS and why does it bind to the membrane? 19. In the insulin signal transduction pathway that leads to increases in the diacylglycerol and inositoltrisphosphate second messengers, What is the first signal transducer protein that binds to the IRS? Why does it bind to the IRS. 20. Explain the sequence of reactions that occur following the binding of glucagon or epinephrine to a heptahelical receptor. Include the terms: glucagon, epinephrine, heterotrimeric G proteins, a subunit, bg complex, GDP, GTP, tethered, lipid anchor, adenylyl cyclase, ATP, cAMP, PPi, and hydrolysis How long does the Gas protein stay active? 21. What is the effect of activating Gas, Gai , or Gaq? 22. A mutated form of the G-protein Ras is found in many cancers. How are these mutations thought to affect the cell? Use the term internal clock in your answer. 23. What is the response when epinephrine binds to an a1-adrenergic receptor? What is the response when epinephrine binds to a b-receptor? That is, what kind of G-protein is activated and what are the initial second messengers produced? 24. Name the enzyme that synthesizes cAMP, the enzyme that hydrolyses cAMP and the enzyme that is activated allosterically by cAMP. Which of these three enzyme reactions is affected by insulin? 25. When phosphatidyl inositol bisphosphate is hydrolyzed by phospholipase C, what is the next step in the signal transduction pathway for diacylglycerol? What are the next several steps in the signal transduction pathway for inositol trisphosphate? Use protein kinase C, target proteins, endoplasmic reticulum, calcium, calmodulin, and calmodulin binding proteins in your answer. 26. Glucagon is released when blood sugar is low. How is its signal terminated (or lowered) following a high carbohydrate meal that increases the blood sugar? 27. Concerning Mya Sthenia who has myasthenia gravis, explain how her chemical messenger system differs from a normal person. How did this happen? Why do the anticholinesterase drugs do to temporarily alleviate the problem? 28. Concerning Ann O'Rexia who has been fasting and is jogging, what was the stimulus for the release of glucagon, epinephrine, norepinephrine, and cortisol? From what cells and what tissue did glucagon originate? From what tissues did epinephrine, norepinephrine, and cortisol originate? What is the effect of all these hormones upon the release of glucose from liver and free fatty acids from adipose tissue? 29. Concerning Ann O'Rexia who has been fasting, why is her blood glucagon increased? Why does glucagon have an effect upon adipose and liver tissue but not upon skeletal muscle tissue? 30. Concerning Ann O'Rexia, do glucagon, epinephrine, norepinephrine, and cortisol react with the same receptors, use the same pathways, and elicit the same cellular response? 31. Concerning Ann O'Rexia, what are the two general mechanisms (ways) that glucagon, epinephrine and other hormones use to elicit a response in target cells? 32. Concerning Dennis Veere who has cholera, how does the cholera A toxin change the metabolism of the intestinal cell? Use ADP-ribosylation factor, NAD, ADP ribose, ADP-ribosylates, Gas subunit, adenyl cyclase, cAMP, CFTR channel, chloride ion, sodium, and diarrhea in your answer. 33. Understand the meaning of each of the keywords. KEYWORDS: a-cells, a subunit, acetylcholine, acetylcholinesterase, action potential, ADP ribose, ADP-ribosylate, adenylyl cyclase, adrenal cortex, adrenal medulla, autophosphorylate, autocrine, autoimmune, disease, b receptor, cAMP, cAMP phosphodiesterase, Ca2+ channel, calmodulin, CFTR channel, chloride ion, cortisol, diacylglycerol (DAG), endocrine, endoplasmic reticulum, epinephrine, fusion, Gai, Gaq, Gas, GDP, GTP, gated ion channel, glucagon, gluconeogenesis, glycogenolysis, Grb2, heterotrimeric G protein, inositol 1,4,5-trisphosphate (IP3), insulin, insulin receptor, substrate, "internal clock," membrane spanning, Na+, NAD, norepinephrine, pancreas, paracrine, phosphatidylinositol 3,4,5 trisphosphate (PI-3,4,5-trisP), phospholipase C, PI 3-kinase, pleckstrin homology, postsynaptic membrane, protein kinase A, protein kinase C, SH2 domain, signal transduction pathway, signal transducer proteins, subunit, synapse, tethered, transcription, tyrosine kinase domain, vesicle. ASSIGNMENTS: Examine questions in chapter 11 Work questions 1, 2, and 5. Not 3 and 4 at the end of Chapter 11 No questions are assigned questions in the Board Review Book. Understand the meaning of the key words in the context of Chapter 11 Practice Questions for Chapter 11 Objectives No Other Help REFERENCE: Marks’ Basic Medical Biochemistry: A Clinical Approach, 2nd Edition, 2004, Williams and Wilkins (ISBN: 0-7817-2145-8) by Colleen M. Smith PhD, Allan D. Marks MD, and Michael A. Lieberman PhD