1. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Overview: The Cellular Internet Cell-to-cell communication is essential for multicellular organisms Biologists have discovered some universal mechanisms of cellular regulation

2. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Evolution of Cell Signaling A signal-transduction pathway is a series of steps by which a signal on a cell’s surface is converted into a specific cellular response Signal transduction pathways convert signals on a cell’s surface into cellular responses Pathway similarities suggest that ancestral signaling molecules evolved in prokaryotes and have since been adopted by eukaryotes

3. LE 11-2 Exchange of mating factors Mating Receptor a   factor a  a factor Yeast cell, mating type a Yeast cell, mating type  a/  New a/  cell

4. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Local and Long-Distance Signaling Cells in a multicellular organisms communicate by chemical messengers Animal and plant cells have cell junctions that directly connect the cytoplasm of adjacent cells In local signaling, animal cells may communicate by direct contact

5. LE 11-3 Plasma membranes Gap junctions between animal cells Cell junctions Cell-cell recognition Plasmodesmata between plant cells

6. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings In many other cases, animal cells communicate using local regulators, messenger molecules that travel only short distances In long-distance signaling, plants and animals use chemicals called hormones

7. LE 11-4 Paracrine signaling Local regulator diffuses through extracellular fluid Secretory vesicle Secreting cell Target cell Local signaling Electrical signal along nerve cell triggers release of neurotransmitter Neurotransmitter diffuses across synapse Endocrine cell Blood vessel Long-distance signaling Hormone travels in bloodstream to target cells Synaptic signaling Target cell is stimulated Hormonal signaling Target cell

8. Concept 5.5 The Membrane Plays a Key Role in a Cell’s Response to Environmental Signals Cells are exposed to many signals and may have different responses: Autocrine signals affect the same cells that release them. Paracrine signals diffuse to and affect nearby cells. Hormones travel to distant cells.

9. Figure 5.10 Chemical Signaling Concepts

10. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings The Three Stages of Cell Signaling: A Preview Sutherland suggested that cells receiving signals went through three processes: – Reception – Transduction – Response Animation: Overview of Cell Signaling Animation: Overview of Cell Signaling

11. LE 11-5_3 EXTRACELLULAR FLUID Reception Plasma membrane Transduction CYTOPLASM Receptor Signal molecule Relay molecules in a signal transduction pathway Response Activation of cellular response

12. Figure 5.11 Signal Transduction Concepts

13. RECEPTION

14. Concept 5.5 The Membrane Plays a Key Role in a Cell’s Response to Environmental Signals Only cells with the necessary receptors can respond to a signal— the target cell must be able to sense it and respond to it. A signal transduction pathway involves a signal, a receptor, and a response.

15. Figure 5.12 A Signal Binds to Its Receptor

16. Figure 5.11 Signal Transduction Concepts

17. Concept 5.5 The Membrane Plays a Key Role in a Cell’s Response to Environmental Signals A signal molecule, or ligand, fits into a three-dimensional site on the receptor protein. Binding of the ligand causes the receptor to change its three-dimensional shape. The change in shape initiates a cellular response.

18. Concept 5.5 The Membrane Plays a Key Role in a Cell’s Response to Environmental Signals Receptors can be classified by their location in the cell. This is determined by whether or not their ligand can diffuse through the membrane.

19. Concept 5.5 The Membrane Plays a Key Role in a Cell’s Response to Environmental Signals Cytoplasmic receptors have ligands, such as estrogen, that are small or nonpolar and can diffuse across the membrane. Membrane receptors have large or polar ligands, such as insulin, that cannot diffuse and must bind to a transmembrane receptor at an extracellular site.

20. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Intracellular Receptors Some receptor proteins are intracellular, found in the cytosol or nucleus of target cells Small or hydrophobic chemical messengers can readily cross the membrane and activate receptors Examples of hydrophobic messengers are the steroid and thyroid hormones of animals An activated hormone-receptor complex can act as a transcription factor, turning on specific genes

21. LE 11-6 EXTRACELLULAR FLUID Plasma membrane The steroid hormone testosterone passes through the plasma membrane. Testosterone binds to a receptor protein in the cytoplasm, activating it. The hormone- receptor complex enters the nucleus and binds to specific genes. The bound protein stimulates the transcription of the gene into mRNA. The mRNA is translated into a specific protein. CYTOPLASM NUCLEUS DNA Hormone (testosterone) Receptor protein Hormone- receptor complex mRNA New protein

22. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Receptors in the Plasma Membrane Most water-soluble signal molecules bind to specific sites on receptor proteins in the plasma membrane There are three main types of membrane receptors: – G-protein-linked receptors – Protein kinase receptors – Ion channel receptors

23. Concept 5.5 The Membrane Plays a Key Role in a Cell’s Response to Environmental Signals Ion channel receptors, or gated ion channels, change their three- dimensional shape when a ligand binds. The acetylcholine receptor, a ligand- gated sodium channel, binds acetylcholine to open the channel and allow Na + to diffuse into the cell.

24. LE 11-7c Signal molecule (ligand) Gate closed Ions Ligand-gated ion channel receptor Plasma membrane Gate closed Gate open Cellular response

25. Concept 5.5 The Membrane Plays a Key Role in a Cell’s Response to Environmental Signals Protein kinase receptors change their shape when a ligand binds. The new shape exposes or activates a cytoplasmic domain that has catalytic (protein kinase) activity.

26. Concept 5.5 The Membrane Plays a Key Role in a Cell’s Response to Environmental Signals Protein kinases catalyze the following reaction: ATP + protein  ADP + phosphorylated protein Each protein kinase has a specific target protein, whose activity is changed when it is phosphorylated.

27. Figure 5.13 A Protein Kinase Receptor

28. Concept 5.5 The Membrane Plays a Key Role in a Cell’s Response to Environmental Signals Ligands binding to G protein–linked receptors expose a site that can bind to a membrane protein, a G protein. The G protein is partially inserted in the lipid bilayer, and partially exposed on the cytoplasmic surface.

29. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings A G-protein-linked receptor is a plasma membrane receptor that works with the help of a G protein The G-protein acts as an on/off switch: If GDP is bound to the G protein, the G protein is inactive

30. Concept 5.5 The Membrane Plays a Key Role in a Cell’s Response to Environmental Signals Many G proteins have three subunits and can bind three molecules: The receptor GDP and GTP, used for energy transfer An effector protein to cause an effect in the cell

31. Figure 5.14 A G Protein–Linked Receptor

32. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Protein Phosphorylation and Dephosphorylation In many pathways, the signal is transmitted by a cascade of protein phosphorylations Phosphatase enzymes remove the phosphates This phosphorylation and dephosphorylation system acts as a molecular switch, turning activities on and off

33. LE 11-8 Signal molecule Activated relay molecule Receptor Inactive protein kinase 1 Active protein kinase 1 Inactive protein kinase 2 Active protein kinase 2 Inactive protein kinase 3 Active protein kinase 3 ADP Inactive protein Active protein Cellular response Phosphorylation cascade ATP PP P i ADP ATP PP P i ADP ATP PP P i P P P

34. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Transduction of Signals - Why bother with Signal Transduction Cascades?

35. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Transduction: Cascades of molecular interactions relay signals from receptors to target molecules in the cell Transduction usually involves multiple steps Multistep pathways can amplify a signal: A few molecules can produce a large cellular response Multistep pathways provide more opportunities for coordination and regulation

36. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Signal Transduction Pathways The molecules that relay a signal from receptor to response are mostly proteins Like falling dominoes, the receptor activates another protein, which activates another, and so on, until the protein producing the response is activated At each step, the signal is transduced into a different form, usually a conformational change

37. LE 11-13 Binding of epinephrine to G-protein-linked receptor (1 molecule) Reception Transduction Inactive G protein Active G protein (10 2 molecules) Inactive adenylyl cyclase Active adenylyl cyclase (10 2 ) ATP Cyclic AMP (10 4 ) Inactive protein kinase A Inactive phosphorylase kinase Active protein kinase A (10 4 ) Active phosphorylase kinase (10 5 ) Active glycogen phosphorylase (10 6 ) Inactive glycogen phosphorylase Glycogen Response Glucose-1-phosphate (10 8 molecules)

38. Concept 5.6 Signal Transduction Allows the Cell to Respond to Its Environment A second messenger is an intermediary between the receptor and the cascade of responses. Second messengers allow the cell to respond to a single membrane event with many events inside the cell—they distribute the signal. They amplify the signal by activating more than one enzyme target.

39. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Small Molecules and Ions as Second Messengers Second messengers are small, nonprotein, water- soluble molecules or ions The extracellular signal molecule that binds to the membrane is a pathway’s “first messenger” Second messengers can readily spread throughout cells by diffusion Second messengers participate in pathways initiated by G-protein-linked receptors and receptor tyrosine kinases

40. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Cyclic AMP Cyclic AMP (cAMP) is one of the most widely used second messengers Adenylyl cyclase, an enzyme in the plasma membrane, converts ATP to cAMP in response to an extracellular signal

41. Figure 5.16 The Formation of Cyclic AMP

42. LE 11-10 cAMP ATP Second messenger First messenger (signal molecule such as epinephrine) G-protein-linked receptor G protein Adenylyl cyclase Protein kinase A Cellular responses GTP

43. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Calcium ions and Inositol Triphosphate (IP 3 ) Calcium ions (Ca 2+ ) act as a second messenger in many pathways Calcium is an important second messenger because cells can regulate its concentration

44. LE 11-11 ATP EXTRACELLULAR FLUID ATP Mitochondrion Ca 2+ pump Plasma membrane CYTOSOL Endoplasmic reticulum (ER) Ca 2+ pump Ca 2+ pump High [Ca 2+ ] Key Nucleus Low [Ca 2+ ]

45. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings A signal relayed by a signal transduction pathway may trigger an increase in calcium in the cytosol Pathways leading to the release of calcium involve inositol triphosphate (IP 3 ) and diacylglycerol (DAG) as second messengers Animation: Signal Transduction Pathways Animation: Signal Transduction Pathways

46. LE 11-12_1 CYTOSOL Ca 2+ Endoplasmic reticulum (ER) IP 3 -gated calcium channel IP 3 (second messenger) DAG PIP 2 G-protein-linked receptor Phospholipase C G protein Signal molecule (first messenger) EXTRACELLULAR FLUID GTP

47. LE 11-12_2 CYTOSOL Ca 2+ Endoplasmic reticulum (ER) IP 3 -gated calcium channel IP 3 (second messenger) DAG PIP 2 G-protein-linked receptor Phospholipase C G protein Signal molecule (first messenger) EXTRACELLULAR FLUID GTP Ca 2+ (second messenger)

48. LE 11-12_3 CYTOSOL Ca 2+ Endoplasmic reticulum (ER) IP 3 -gated calcium channel IP 3 (second messenger) DAG PIP 2 G-protein-linked receptor Phospholipase C G protein Signal molecule (first messenger) EXTRACELLULAR FLUID GTP Ca 2+ (second messenger) Various proteins activated Cellular re- sponses

49. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Response

50. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Concept 11.4: Response: Cell signaling leads to regulation of cytoplasmic activities or transcription The cell’s response to an extracellular signal is sometimes called the “output response” Ultimately, a signal transduction pathway leads to regulation of one or more cellular activities The response may occur in the cytoplasm or may involve action in the nucleus Many pathways regulate the activity of enzymes

51. Concept 5.6 Signal Transduction Allows the Cell to Respond to Its Environment Cell functions change in response to environmental signals: Opening of ion channels Alterations in gene expression Alteration of enzyme activities

52. Concept 5.6 Signal Transduction Allows the Cell to Respond to Its Environment Cells can alter the balance of enzymes in two ways: Synthesis or breakdown of the enzyme Activation or inhibition of the enzymes by other molecules

53. Concept 5.6 Signal Transduction Allows the Cell to Respond to Its Environment Signal transduction ends after the cell responds—enzymes convert each transducer back to its inactive precursor. The balance between the regulating enzymes and the signal enzymes determines the cell’s response.

54. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Termination of the Signal Inactivation mechanisms are an essential aspect of cell signaling When signal molecules leave the receptor, the receptor reverts to its inactive state

55. Figure 5.18 Signal Transduction Regulatory Mechanisms

56. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings The Specificity of Cell Signaling Different kinds of cells have different collections of proteins These differences in proteins give each kind of cell specificity in detecting and responding to signals The response of a cell to a signal depends on the cell’s particular collection of proteins Pathway branching and “cross-talk” further help the cell coordinate incoming signals

57. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Fine-Tuning of the Response Multistep pathways have two important benefits: – Amplifying the signal (and thus the response) – Contributing to the specificity of the response

58. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Examples of Signal Transduction Ion-channel receptor: acetylcholine-Na+ channel G-protein coupled receptor: epinephrine Protein Kinase receptor: insulin and quorum sensing

59. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Insulin Signaling in Muscle

60. Epinephrine Signaling in Liver cells Signal transduction pathways involve multiple steps—enzymes may be either activated or inhibited by other enzymes. In liver cells, a signal cascade begins when epinephrine stimulates a G protein–mediated protein kinase pathway.

61. Epinephrine Signaling in Liver Epinephrine binds to its receptor and activates a G protein. cAMP is produced and activates protein kinase A—it phosphorylates two other enzymes, with opposite effects: Inhibition Activation

62. Figure 5.17 A Cascade of Reactions Leads to Altered Enzyme Activity (Part 1)

63. Figure 5.17 A Cascade of Reactions Leads to Altered Enzyme Activity (Part 2)

64. Concept 5.6 Signal Transduction Allows the Cell to Respond to Its Environment Inhibition—protein kinase A inactivates glycogen synthase through phosphorylation, and prevents glucose storage. Activation—Phosphorylase kinase is activated when phosphorylated and is part of a cascade that results in the liberation of glucose molecules.