Chapter 11

1. Chapter 11 Cell Communication

2. Overview: The Cellular Internet • Cell-to-cell communication is essential for multicellular organisms • Biologists have discovered some universal mechanisms of cellular regulation • The combined effects of multiple signals determine cell response • For example, the dilation of blood vessels is controlled by multiple molecules

3. Viagra • Microbes are a window on the role of cell signaling in the evolution of life Figure 11.1

4. Exchange of mating factors. Each cell type secretes a mating factor that binds to receptors on the other cell type. factor 3 1 2 Receptor a  factor Yeast cell, mating type a Yeast cell, mating type Mating. Binding of the factors to     receptors induces changes      in the cells that     lead to their     fusion.  a New a/ cell. The nucleus of the fused cell includes all the genes from the a and a cells. a/ Figure 11.2 Evolution of Cell Signaling • Yeast cells identify their mates by cell signaling

5. Signal transduction pathways • Convert specific signals on a cell’s surface into cellular responses • Often a series of steps • Molecular details of signal transduction in yeast, mammals, bacteria and plants are very similar...

6. Evolution of signal transduction pathways • Even though the last common ancestor was over a billion years ago • This suggest early versions of cell signaling developed in the ancient prokaryotes • Before first multicellular organisms

7. Fig. 11-3 Individual rod- shaped cells 1 2 Aggregation in process 0.5 mm Spore-forming structure (fruiting body) 3 Fruiting bodies

8. Local and Long-Distance and Signaling • Cells in a multicellular organism • Usually communicate via chemical messengers • Direct contact • Local signaling • Long-distance signaling

9. Plasma membranes Plasmodesmata between plant cells Gap junctions between animal cells Figure 11.3 (a) Cell junctions. Both animals and plants have cell junctions that allow molecules to pass readily between adjacent cells without crossing plasma membranes. Direct contact - Cell junctions • Animal and plant cells can directly connect the cytoplasm of adjacent cells

10. Figure 11.3 (b) Cell-cell recognition. Two cells in an animal may communicate by interaction between molecules protruding from their surfaces. Direct contact - Cell-cell recognition • In local signaling, animal cells may communicate via direct contact

11. Local signaling Target cell Electrical signal along nerve cell triggers release of neurotransmitter Neurotransmitter diffuses acrosssynapse Secretory vesicle Local regulator diffuses through extracellular fluid Target cell is stimulated (b) Synaptic signaling. A nerve cell releases neurotransmitter molecules into a synapse, stimulating the target cell. (a) Paracrine signaling. A secreting cell acts on nearby target cells by discharging molecules of a local regulator (a growth factor, for example) into the extracellular fluid. Figure 11.4 A B Local – Paracrine & Synaptic • Animal cells communicate using local regulators

12. Long-distance signaling Blood vessel Endocrine cell Hormone travels in bloodstream to target cells Target cell (c) Hormonal signaling. Specialized endocrine cells secrete hormones into body fluids, often the blood. Hormones may reach virtually all body cells. Figure 11.4 C Long-distance signaling • Both plants and animals use hormones

13. The Three Stages of Cell Signaling: A Preview • Earl W. Sutherland • Discovered how the hormone epinephrine acts on cells • Epinephrine stimulates glycogen breakdown • The enzyme (glycogen phosphorylase) does not work with an intact cellular membrane

14. Cellular conversation • Sutherland suggested that cells receiving signals went through three processes • Reception • Transduction • Response Animation: Overview of Cell Signaling

15. EXTRACELLULAR FLUID CYTOPLASM Plasma membrane 1 2 3 Reception Transduction Response Receptor Activation of cellular response Relay molecules in a signal transduction pathway Signal molecule Figure 11.5 Overview of cell signaling

16. Concept 11.2: Reception: A signal molecule binds to a receptor protein, causing it to change shape • The binding between signal molecule (ligand) • And receptor is highly specific • A conformational change in a receptor • Is often the initial transduction of the signal

17. Receptors in the Plasma Membrane • Most water-soluble signal molecules bind to specific receptor proteins in membrane • There are three main types of membrane receptors • G protein-coupled receptors • Receptor tyrosine kinases • Ion channel receptors

18. G protein-coupled receptors • A G protein-coupled 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

19. Fig. 11-7b Plasma membrane Inactive enzyme G protein-coupled receptor Signaling molecule Activated receptor GDP GTP GDP Enzyme G protein (inactive) CYTOPLASM 2 1 Activated enzyme GTP GDP P i Cellular response 4 3

20. G protein-coupled receptors • Large family of eukaryotic receptor proteins • They function is diverse and widespread • For example, embryo development and sensory reception • Bacteria like cholera, pertussis and botulism interfere with G-protein function • 60% of all medicines exert effects on G-proteins

21. Signal-binding sitea Signalmolecule Signal molecule Helix in the Membrane Tyr Tyr Tyr Tyr Tyrosines Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Receptor tyrosinekinase proteins(inactive monomers) Dimer CYTOPLASM Activatedrelay proteins Cellularresponse 1 Tyr Tyr Tyr Tyr Tyr Tyr P P Tyr P Tyr Tyr Tyr Tyr P Tyr Tyr Tyr P P P Tyr Tyr Tyr Tyr Tyr P Tyr Tyr Tyr Cellularresponse 2 P P P Tyr Tyr P 6 ATP 6 ADP Activated tyrosine- kinase regions (unphosphorylated dimer) Fully activated receptor tyrosine-kinase (phosphorylated dimer) Inactiverelay proteins Figure 11.7 Receptor tyrosine kinases

22. Receptor tyrosine kinases • Receptor tyrosine kinases are membrane receptors that attach phosphates to tyrosines • They may activate 10 or more different transduction pathways and cellular responses • Abnormal receptor tyrosine kinases may contribute to some cancers

23. Ion channel receptors 1 Signaling molecule (ligand) Gate closed Ions Plasma membrane Ligand-gated ion channel receptor 2 Gate open Cellular response 3 Gate closed

24. Ligand-gated ion channel • The gate allows or blocks the flow of specific ions, such as Na+ and Ca2+ • Important in the nervous system • The signal molecule can be a ligand (as shown in the picture) or an electrical signal

25. Intracellular Receptors • Intracellular receptors • Are cytoplasmic or nuclear proteins • Signal molecules that are small or hydrophobic • And can readily cross the plasma membrane use these receptors

26. Hormone (testosterone) EXTRACELLULAR FLUID 1 The steroid hormone testosterone passes through the plasma membrane. Plasma membrane Receptor protein 2 Testosterone binds to a receptor protein in the cytoplasm, activating it. Hormone- receptor complex 3 The hormone- receptor complex enters the nucleus and binds to specific genes. DNA mRNA 4 The bound protein stimulates the transcription of the gene into mRNA. NUCLEUS New protein 5 The mRNA is translated into a specific protein. CYTOPLASM Figure 11.6 Steroid hormones • Bind to intracellular receptors • The testosterone receptor acts as a transcription factor • Most intracellular receptors work this way

27. Concept 11.3: Transduction: Cascades of molecular interactions relay signals from receptors to target molecules in the cell • Signal 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 of the cellular response

28. 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 shape change in a protein

29. Protein phosphorylation & dephosphorylation • In many pathways, the signal is transmitted by a cascade of protein phosphorylations • Protein kinases transfer phosphates from ATP to protein, a process called phosphorylation • Cytoplasmic protein kinases phosphorylate either amino acid serine or threonine (rather than tyrosine) • Serine/threonine kinases are involved in signaling pathways in animals, plants and fungi

30. In this process • A series of protein kinases add a phosphate to the next one in line, activating it • Protein phosphatase (PP) enzymes then remove the phosphates • Phosphorylation/dephosphorylation system acts as a molecular switch • turning activities on and off

31. Signal molecule A relay molecule activates protein kinase 1. Receptor Activated relay molecule 4 1 3 5 2 Inactive protein kinase 1 Active protein kinase 1 transfers a phosphate from ATP to an inactive molecule of protein kinase 2, thus activating this second kinase. Active protein kinase 1 Active protein kinase 2 then catalyzes the phos- phorylation (and activation) of protein kinase 3. Inactive protein kinase 2 ATP Phosphorylation cascade P Active protein kinase 2 ADP PP P i Enzymes called protein phosphatases (PP) catalyze the removal of the phosphate groups from the proteins, making them inactive and available for reuse. Inactive protein kinase 3 Finally, active protein kinase 3 phosphorylates a protein (pink) that brings about the cell’s response to the signal. ATP P ADP Active protein kinase 3 PP P i Inactive protein ATP P ADP Active protein Cellular response PP P  i A phosphorylation cascade Figure 11.8

32. Small Molecules and Ions as Second Messengers • Second messengers • Are small, nonprotein, water-soluble molecules or ions • Two most widely used second messengers are: • Cyclic AMP (cAMP) • Calcium ions, Ca2+

33. NH2 NH2 NH2 N N N N N N N N N N N O O O N O Adenylyl cyclase Phoshodiesterase CH2 O HO Ch2 P –O O P O P P O CH2 O O O O O O O O O P Pyrophosphate H2O O O P P i OH OH OH OH OH ATP Cyclic AMP AMP Figure 11.9 Cyclic AMP • Cyclic AMP (cAMP) • Is made from ATP

34. First messenger (signal molecule such as epinephrine) Adenylyl cyclase G protein GTP G-protein-linked receptor ATP cAMP Protein kinase A Cellular responses Many G-proteins • Trigger the formation of cAMP, which then acts as a second messenger in cellular pathways Figure 11.10

35. Calcium ions and Inositol Triphosphate (IP3) • Ca2+, when released into the cytosol of a cell • Acts as a second messenger • Animal cells – muscle contraction, secretion of certain substances and cell division • Plant cells – hormonal and environmental stimuli can cause changes in Ca2+ concentration signaling various pathways

36. EXTRACELLULAR FLUID Plasma membrane Ca2+pump ATP Mitochondrion Nucleus CYTOSOL Ca2+pump Endoplasmic reticulum (ER) ATP Ca2+pump Key High [Ca2+] Low [Ca2+] Figure 11.11 Calcium is an important second messenger • Because cells are able to regulate its concentration in the cytosol

37. Other second messengers • Such as inositol triphosphate (IP3) and diacylglycerol (DAG) • Can trigger an increase in calcium in the cytosol Animation: Signal Transduction Pathways

38. Fig. 11-13-3 EXTRA- CELLULAR FLUID Signaling molecule (first messenger) G protein DAG GTP G protein-coupled receptor PIP2 Phospholipase C IP3 (second messenger) IP3-gated calcium channel Endoplasmic reticulum (ER) Various proteins activated Cellular responses Ca2+ Ca2+ (second messenger) CYTOSOL

39. Cytoplasmic & nuclear responses • In the cytoplasm • Signaling pathways regulate a variety of cellular activities • They regulate the activity of enzymes • They also regulate the synthesis of enzymes or other proteins, usually by turning genes on or off in the nucleus • The final activated molecule may function as a transcription factor

40. Growth factor Reception Receptor Phosphorylation cascade Transduction CYTOPLASM Inactive transcription factor Active transcription factor Response P DNA Gene mRNA NUCLEUS Figure 11.14 Nuclear responses to a signal • Regulate genes by activating transcription factors that turn genes on or off

41. Reception Binding of epinephrine to G-protein-linked receptor (1 molecule) Transduction Inactive G protein Active G protein (102 molecules) Inactive adenylyl cyclase Active adenylyl cyclase (102) ATP Cyclic AMP (104) Inactive protein kinase A Active protein kinase A (104) Inactive phosphorylase kinase Active phosphorylase kinase (105) Inactive glycogen phosphorylase Active glycogen phosphorylase (106) Response Glycogen Glucose-1-phosphate(108 molecules) Cytoplasmic response to a signal • Regulating the activity of enzymes • The stimulation of glycogen breakdown by epinephrine Figure 11.13

42. Signaling events may also affect cellular attributes • such as overall cell shape. • One example of this regulation can be found in the activities leading to the mating of yeast cells. • In yeast, the mating process depends on the growth of localized projections in one cell toward a cell of the opposite mating type.

43. Fig. 11-16 RESULTS Wild-type (shmoos) ∆Fus3 ∆formin CONCLUSION Mating factor Shmoo projection forming 1 G protein-coupled receptor Formin P Fus3 Actin subunit GTP P GDP Phosphory- lation cascade 2 Formin Formin P 4 Microfilament Fus3 Fus3 P 5 3

44. 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

45. Signal Amplification • Enzyme cascades amplify the cell’s response • At each step, the number of activated products is much greater than in the preceding step

46. The Specificity of Cell Signaling • Different kinds of cells have different collections of proteins • These different proteins allow cells to detect and respond to different signals • Even the same signal can have different effects in cells with different proteins and pathways • Pathway branching and “cross-talk” further help the cell coordinate incoming signals

47. Signalmolecule Receptor Relaymolecules Response 2 Response 1 Response 3 Cell B. Pathway branches, leading to two responses Cell A. Pathway leads to a single response Activationor inhibition Response 4 Response 5 Cell C. Cross-talk occurs between two pathways Cell D. Different receptor leads to a different response Figure 11.15 Specificity of cell signaling

48. Epinephrine • A small number of epinephrine molecules can lead to the release of hundreds of millions of glucose molecules from glycogen • Epinephrine stimulates the liver to break down glycogen, but the heart cell to contract

49. Signaling Efficiency: Scaffolding Proteins & Signaling Complexes • Scaffolding proteins are large relay proteins to which other relay proteins are attached • Scaffolding proteins can increase the signal transduction efficiency by grouping together different proteins involved in the same pathway

50. Signalmolecule Plasmamembrane Receptor Threedifferentproteinkinases Scaffoldingprotein Figure 11.16 Signaling Efficiency: Scaffolding Proteins and Signaling Complexes • Scaffolding proteins • Can increase the signal transduction efficiency