1. Cell-Cell Communication

2. Overview: Cellular Signaling Cells communicate with each other via chemical signals. For example, the fight-or-flight response is triggered by a signaling molecule called epinephrine Cell-to-cell communication is essential for both multicellular and unicellular organisms Biologists have discovered some universal mechanisms of cellular communication © 2011 Pearson Education, Inc.

3. Cell Signaling by Multicellular Organisms Coordinates activities within individual cells to support the function of the organism as a whole Examples: –Response to DNA damage Could lead to expression of mutant proteins and cellular dysfunction and/or cancer if unchecked Cell signaling pathways prevent this by activating DNA repair enzymes or initiating programmed cell death (apoptosis) © 2011 Pearson Education, Inc.

4. Local Signaling In local signaling, cells within multicellular organisms may communicate by: –contact through the cytoplasm of adjacent cells cell junctions –cell-cell contact Ligand on one cell binds to a receptor on an adjacent cell –short range signals Cell secretes a soluble ligand that binds to a receptor on a nearby cell © 2011 Pearson Education, Inc.

5. Local Signaling: Cytoplasmic contact at cell junctions Cell-cell contact between adjacent cells involving membrane bound ligands

6. Local signaling Target cell Secreting cell Secretory vesicle Local regulator diffuses through extracellular fluid. (a) Paracrine signaling (b) Synaptic signaling Electrical signal along nerve cell triggers release of neurotransmitter. Neurotransmitter diffuses across synapse. Target cell is stimulated. Short range signals involving soluble ligands

7. Long-Distance Signaling In long distance signaling, cells within multicellular organisms may communicate use chemicals called hormones –synthesized by cells in one region of the body –travel through the bloodstream to reach their cellular targets in other regions of the body © 2011 Pearson Education, Inc.

8. Figure 11.5b Long-distance signaling Endocrine cell Blood vessel Hormone travels in bloodstream. Target cell specifically binds hormone. (c) Endocrine (hormonal) signaling

9. Only the signaling molecule that fits the shape of a specific receptor can trigger a response in a cell Mediated by shape and chemical nature of interacting regions Different cell types produce different receptors A cell synthesizes many different kinds of receptors, depending on conditions or stages in its life cycle The same signal can have different meanings for various target cells © 2011 Pearson Education, Inc. Signal Specificity and Cell Specialization

10. The Three Stages of Cell Signaling: (within 1 cell) 1)Reception 2)Transduction 3)Response © 2011 Pearson Education, Inc.

11. Figure 11.6-1 Plasma membrane EXTRACELLULAR FLUID CYTOPLASM Reception Receptor Signaling molecule 1

12. Figure 11.6-2 Plasma membrane EXTRACELLULAR FLUID CYTOPLASM ReceptionTransduction Receptor Signaling molecule Relay molecules in a signal transduction pathway 2 1

13. Figure 11.6-3 Plasma membrane EXTRACELLULAR FLUID CYTOPLASM ReceptionTransduction Response Receptor Signaling molecule Activation of cellular response Relay molecules in a signal transduction pathway 3 2 1

14. Step 1: Signal Reception A signaling molecule binds to a receptor protein, causing it to change shape, and initiating the transduction of the signal Most receptors are plasma membrane proteins but some are inside of the cell (cytoplasmic/nuclear receptors) The binding between a signal molecule (ligand) and receptor is highly specific © 2011 Pearson Education, Inc.

15. Cell Surface and Intracellular Receptors

16. Receptors in the Plasma Membrane There are three main types of membrane receptors –Ion channel receptors –G protein-coupled (linked) receptors –Protein kinase receptors (aka receptor tyrosine kinases) © 2011 Pearson Education, Inc.

17. A ligand-gated ion channel receptor acts as a gate When a ligand binds to the receptor, the shape changes, allowing specific ions, such as Na + or Ca 2+, to pass into the cell through a channel in the receptor © 2011 Pearson Education, Inc. Ligand-Gated Ion Channel Receptors

18. Fig. 6-5a, p. 140 Signaling molecule Extracellular fluid Na + Receptor Cytosol Ion channel is closed. 12 When signaling molecule binds to receptor, the channel changes shape and opens. Sodium ions enter the cell. Ligand-Gated Ion Channel Receptors

19. A GPCR is a plasma membrane receptor that works with the help of a G protein, located in the cytoplasm Upon ligand binding the G protein is turned on by the exchange of GDP for GTP The G protein then helps to transmit the intracellular signal © 2011 Pearson Education, Inc. G Protein Linked Receptors

20. Fig. 6-5b, p. 140 Signaling molecule Receptor G proteinEnzyme Cytosol GDP GTP Inactive state: the three subunits of G protein are joined and it is bound to GDP 12 Ligand binding: receptor binds to G protein causing GDP to be replaced with GTP and the separation of one subunit. This is the active state. G Protein Coupled Receptors

21. PKRs are membrane receptors that also have enzymatic activity transfer phosphate groups (phosphorylation) from ATP to specific tyrosine residues on proteins A receptor tyrosine kinase can trigger multiple signal transduction pathways at once Abnormal functioning of PKRs is associated with many types of cancers © 2011 Pearson Education, Inc. Protein Kinase Receptors

22. Signaling molecule (ligand) 2 1 34 Ligand-binding site  helix in the membrane Tyrosines CYTOPLASM Receptor tyrosine kinase proteins (inactive monomers) Signaling molecule Dimer Tyr P P P P P P P P P P P P Activated tyrosine kinase regions (unphosphorylated dimer) Fully activated receptor tyrosine kinase (phosphorylated dimer) Activated relay proteins Cellular response 1 Cellular response 2 Inactive relay proteins 6 ATP 6 ADP Receptor Tyrosine Kinases

23. Intracellular Receptors © 2011 Pearson Education, Inc. Intracellular receptors are found in the cytosol or nucleus – most are transcription factors that regulate expression of specific genes Signaling molecules are small, hydrophobic molecules that diffuse across the membranes of target cells –Some combine with receptors in the cytosol, then move into the nucleus (e.g. steroid hormones) –Some bind to receptors already bound to DNA inside the nucleus (e.g. thyroid hormones)

24. Hormone (testosterone) Receptor protein Plasma membrane EXTRACELLULAR FLUID Hormone- receptor complex DNA mRNA NUCLEUS CYTOPLASM New protein Steroid hormone interacting with an intracellular receptor

25. Step 2: Signal Transduction Cascades of molecular interactions relay signals from receptors to target molecules in the cell. Signals are relayed by: –Protein kinases –Second messengers Both of these mechanisms help to amplify the signal inside of the cell © 2011 Pearson Education, Inc.

26. Step 2: Signal Transduction Protein kinases help to transmit signals through a cascade of protein phosphorylations –Protein kinases transfer phosphate groups from ATP to other proteins, a process called phosphorylation acts like a molecular on-off switch –The addition of phosphate groups (by kinases)acts like an “on” switch and activates proteins –The removal of phosphate groups (by phosphatases) acts like an “off” switch and de- activates proteins © 2011 Pearson Education, Inc.

27. Receptor Signaling molecule Activated relay molecule Phosphorylation cascade Inactive protein kinase 1 Active protein kinase 1 Active protein kinase 2 Active protein kinase 3 Inactive protein kinase 2 Inactive protein kinase 3 Inactive protein Active protein Cellular response ATP ADP ATP ADP ATP ADP PP P P P P i Figure 11.10 Signal transduction by protein kinases involving a phosphorylation cascade

28. Step 2: Signal Transduction Second messengers –Ions or small molecules that amplify signals inside the cell and relay them to other signaling or target proteins –Ex: cyclic AMP (cAMP), inositol triphosphate (IP 3 ), and calcium ions (Ca 2+ ) © 2011 Pearson Education, Inc.

29. Fig. 6-7, p. 143 Signaling molecule (first messenger) Extracellular fluid Adenylyl cyclase Receptor G protein Plasma membrane Cytosol cAMP Second messenger Protein Alters metabolism Affects gene activity Opens or closes ion channels 1 2 3 Ligand binds to GPCR, activating the G protein and causing one subunit to bind to and activate Adenylyl Cyclase, which then catalyzes formation of cAMP from ATP Signal is amplified and relayed by the second messenger cAMP Response: some cell process is altered

30. Figure 11.14-3 G protein EXTRA- CELLULAR FLUID Signaling molecule (first messenger) G protein-coupled receptor Phospholipase C DAG PIP 2 IP 3 (second messenger) IP 3 -gated calcium channel Endoplasmic reticulum (ER) CYTOSOL Various proteins activated Cellular responses Ca 2  (second messenger) Ca 2  GTP Signaling pathway involving the second messengers IP 3 and Ca 2 

31. 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 © 2011 Pearson Education, Inc.

32. Signal Amplification

33. Step 3: Response Cell signaling leads to regulation of cellular activity including: Opening or closing of ion channels Alteration of enzyme activity, leading to metabolic changes Ex, fight or flight response Alteration of specific gene activity specific proteins made or not made in response Apoptosis © 2011 Pearson Education, Inc.

34. Cellular Response to Signaling

35. Growth factor Receptor Reception Transduction CYTOPLASM Response Inactive transcription factor Active transcription factor DNA NUCLEUS mRNA Gene Phosphorylation cascade P Cellular Response: Activation of a specific gene by a growth factor

36. Termination of the Signal Inactivation mechanisms are an essential aspect of cell signaling If ligand concentration falls, fewer receptors will be bound Unbound receptors revert to an inactive state © 2011 Pearson Education, Inc.

37. How does cell signaling trigger the desperate flight of this gazelle? Link

38. Epinephrine (adrenaline), a hormone, is released by the adrenal gland. It travels through the blood stream to reach its target in muscle or liver cells. There is binds to a G protein coupled receptor and initiates a signaling cascade Results in glucose release by the cells leading to increased heart and breathing rate Fight or Flight Signaling Pathway

39. Fig. 6-9a, p. 144 Epinephrine Extracellular fluid G protein Adenylyl cyclase G protein coupled receptor Plasma membrane Cytosol 1 Fight or Flight Signaling Pathway Reception of Signal

40. Fig. 6-9b, p. 144 Epinephrine G protein coupled receptor G protein separates Adenylyl cyclase 2 Fight or Flight Signaling Pathway Initiation of Signal Transduction

41. Fig. 6-9c, p. 144 Adenylyl cyclase activated G protein coupled Receptor Phosphorylated Protein kinase A Phosphorylated protein (active) Protein Glycogen is broken down into glucose, which is released by the cell. Causes increased blood flow and heart rate as well as increased breathing rate. 3 Ligand: epinephrine Dissociation of activated G protein Fight or Flight Signaling Pathway Cellular Response Animation

42. Apoptosis integrates multiple cell-signaling pathways Apoptosis is programmed or controlled cell suicide Components of the cell are chopped up and packaged into vesicles that are digested by scavenger cells Apoptosis prevents enzymes from leaking out of a dying cell and damaging neighboring cells © 2011 Pearson Education, Inc.

43. Apoptosis evolved early in animal evolution and is essential for the development and maintenance of all animals Apoptosis may be involved in some diseases (for example, Parkinson’s and Alzheimer’s); interference with apoptosis may contribute to some cancers © 2011 Pearson Education, Inc. Role of Apoptosis in Development and Disease

44. Figure 11.22 Interdigital tissue Cells undergoing apoptosis Space between digits 1 mm Role of Apoptosis in Development

45. Evolutionary History of Cell Signaling Similarities in cell communication among diverse organisms suggest that the molecules and mechanisms used in information transfer evolved long ago Evidence suggests that cell communication first evolved in prokaryotes –Some signal transduction pathways found in organisms as diverse as yeasts and animals are quite similar –Highly conserved nature suggests an evolutionary relationship

46. Cellular Signaling and Development Cellular signaling plays a critical role in development and maintenance of multicellular organisms –establishment of body axes –cell fate decisions leading to the formation of germ layers and organ development –maintenance of stem cells within the body

47. Cellular Signaling and Disease Mutations that cause over- or underactive cell signaling can result in disease –diabetes, neurological diseases, autoimmune diseases, cancer Many therapeutic drugs seek to block or balance out over- or underactive signaling pathways –birth control, antihistamines, anti-psychotics, anti-cancer drugs

48. Cellular Signaling and Biotechnology Understanding these pathways allows scientists to modify or manipulate biological systems and cellular physiology –Drugs to treat disease –Control of fruit ripening –Use of growth hormones in poultry, etc –Doping by athletes (EPO, HGH)

49. Helpful Videos/Animations: AP Biology Hayescience “Cell Communication” a general overview- can go back to look at specifics https://www.youtube.com/watch?v=XtN9YjIJhz8https://www.youtube.com/watch?v=XtN9YjIJhz8 Crash Course “Nervous System Part 3: Synapses” a general overview https://www.youtube.com/watch?v=VitFvNvRIIY https://www.youtube.com/watch?v=VitFvNvRIIY Bozeman “Cell Communication” https://www.youtube.com/watch?v=xnGXItWrJ3khttps://www.youtube.com/watch?v=xnGXItWrJ3k Bozeman “Signal Transduction Pathways” https://www.youtube.com/watch?v=qOVkedxDqQo https://www.youtube.com/watch?v=qOVkedxDqQo Life (your textbook): Ch. 7 animations - “Signal Transduction Pathway” & “Signal Transduction & Cancer” http://bcs.whfreeman.com/thelifewire9e/default.asp#542578__591101__ http://bcs.whfreeman.com/thelifewire9e/default.asp#542578__591101__ The Penguin Prof “Signal Transduction” https://www.youtube.com/watch?v=pH_ibPHK0y0https://www.youtube.com/watch?v=pH_ibPHK0y0 Learn Genetics “Fight or Flight Response” example of Signal Transduction http://learn.genetics.utah.edu/content/cells/cellcom/ http://learn.genetics.utah.edu/content/cells/cellcom/ SEE ALSO THE CELL SIGNALING WEBQUEST ACTIVITY FOR ADDITIONAL SPECIFIC SUPPORT VIDEOS/ANIMATIONS.

50. Cell Signaling by Single Celled Organisms Influences how they respond to the environment Examples: –Quorum sensing in bacteria Send and receive signaling relaying info on population density When few organisms present little signaling As numbers increase, more signaling, which can result in different cellular outcomes © 2011 Pearson Education, Inc.

51. Cell Signaling by Single Celled Organisms –Quorum sensing in bacteria Pseudomonas aerginosa live in host without harm until reach a certain population density At high density they form a biofilm and cell signaling changes their gene expression to start producing toxins –Biofilm: A community of microorganisms attached to a solid surface; requires the coordinated activity of numerous bacteria Results in host pathology © 2011 Pearson Education, Inc.

52. Cell Signaling by Single Celled Organisms –Quorum sensing in Pseudomonas aerginosa © 2011 Pearson Education, Inc.

53. Cell Signaling by Single Celled Organisms –Quorum sensing in bacteria Vibrio fischeri is a bioluminescent bacteria that lives in a mutualistic relationship within the light producing organ of a Hawaiian squid In low numbers and with low signaling, bacteria do not synthesize the light producing protein In high numbers and with high signaling, bacteria do synthesize the light producing protein © 2011 Pearson Education, Inc.

54. Cell Signaling by Single Celled Organisms –Quorum sensing in Vibrio fischeri © 2011 Pearson Education, Inc.