Cell Communication: Mechanisms and Signaling Pathways

1. Chapter 11 Cell Communication

2. Cell-to-cell communication • Is absolutely essential for multicellular organisms • Biologists have discovered some universal mechanisms of cellular regulation • cells most often communicate with other cells by chemical signals

3. Concept 11.1: External signals are converted into responses within the cell

4. Signal transduction pathways • Convert signals on a cell’s surface into cellular responses • Are similar in microbes and mammals, suggesting an early origin • Scientists think signaling mechanisms 1st evolved in ancient prokaryotes & unicellular eukaryotes then adopted for new uses by their multicellular descendants

5. Communication involves transduction of stimulatory or inhibitory signals from other cells, organisms or the environment. • Correct and appropriate signal transduction processes are generally under strong selective pressure.

6. Communication Among Bacteria • quorum sensing: bacteria release small molecules detected by like bacteria: gives them a “sense” of local density of cells • allows them to coordinate activities only productive when performed by given # in synchrony • ex: forming a biofilm: aggregation of bacteria adhered to a surface: slime on fallen leaves or on your teeth in the morning (they cause cavities)

7. Biofilm Development

8. Cells can communicate with each other through direct contact with other cells or from a distance via chemical 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 Communication • Animal and plant cells • Have cell junctions that 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 Communication • In local signaling, animal cells • May communicate via direct contact

11. Local Signaling • Cells in a multicellular organism Communicate via chemical messengers • Paracrine signaling • local signaling cells send messages to local regulator cells • synaptic signaling • action potential travels thru cell membrane of neuron triggering exocytosis of neurotransmitter when at axon, NT travels in synapse to receptor site

12. 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 • Communicate using local regulators that target cells in the vicinity of emitting cell.

13. 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 • Endocrine signaling • specialized cells release hormone molecules into vessels of the circulatory system to target cells in other parts of the body

14. The Three Stages of Cell Signaling • Earl W. Sutherland • Discovered how the hormone epinephrine acts on cells by stimulating the breakdown of glycogen within liver and skeletal muscle cells • Sutherland suggested that cells receiving signals went through three processes • Reception • Transduction • Response

15. 3 Stages of Cell Signaling • Reception • target cell’s detection of the signal • Transduction • receptor protein changes converting signal to a form that can bring about specific cellular response via a signal transduction pathway • Response • activation of cellular response

16. 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

17. 11.2 Reception • Signaling begins with the recognition of a chemical messenger by a receptor protein • 1) Intracellular receptors • 2) Receptors in the PM • The signal molecule (ligand) and receptor are highly specific • ex. peptides (short AA chains linked by peptide bonds) • A conformational change in a receptor • Is often the initial transduction of the signal

18. 1) Intracellular Receptors • Intracellular receptors • Are cytoplasmic or nuclear proteins • To reach the receptor, a chemical messenger passes through the target cell’s PM • Ex) steroid hormone testosterone • Signal molecules that are small or hydrophobic • And can readily cross the plasma membrane use these receptors

19. 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 INTRACELLULAR RECEPTORS • In cytoplasm or nucleus of target cell • hydrophobic signaling molecules • Steroid hormones • Bind to intracellular receptors

20. Turning on Genes • special proteins called transcription factors control which genes are turned on • example: • Testosterone (steroid hormone) • its activated receptor acts as transcription factor that turns on specific genes • thus activated receptor carries out transduction of the signal

21. 2) Receptors in the Plasma Membrane • Mostly water-soluble • Transmits information from the extracellular environment to the inside of the cell by changing shape when a specific ligand binds to it • There are three main types of membrane receptors • G-protein-linked receptors • Receptor Tyrosine kinases • Ligand-gated ion channels

22. Signal-binding site Segment that interacts with G proteins Inctivate enzyme ActivatedReceptor G-protein-linked Receptor Signal molecule Plasma Membrane GDP G-protein(inactive) GTP GDP CYTOPLASM Enzyme Activated enzyme GTP GDP Pi Cellular response Figure 11.7 Yeast mating factors, epinephrine & other hormones, embryonic development, sensory reception, human diseases and neurotransmitters • G-protein-linked receptors

23. 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 • Can trigger multiple pathways essential and growth and reproduction • Characterized by having enzymatic activity (kinase) • Membrane receptors that attach phosphates to tyrosines

24. Gate closed Signalmolecule(ligand) Ions Ligand-gated ion channel receptor Plasma Membrane Gate open Cellularresponse Gate close Figure 11.7 • Ion channel receptors • hydrophobic or very small ligands • Signal molecule binds as a ligand to the receptor protein on the extracellular side, the gate opens or closes • examples • steroid hormones & thyroid hormones of animals • Nervous system

25. 11.3 Transduction • Signal transduction is the process by which a signal is converted to a cellular response by a cascades of molecular interactions that relay signals from receptors to target molecules in the cell • Multistep pathways • Can amplify a signal • Provide more opportunities for coordination and regulation • At each step in a pathway • The signal is transduced into a different form, commonly a conformational change in a protein

26. Protein Phosphorylation and Dephosphorylation • Many signal pathways • Include phosphorylation cascades • cascades relay signals from receptors to cell targets, amplifies the signal, results in a response by the cell • Phosphorylation cascades • A series of protein kinases add a phosphate to the next one in line, activating the protein • Then phosphatase enzymes then remove the phosphates, deactivating the protein • Activity depends on the balance in the cell between active kinase and phosphatase molecules • VIDEO

27. 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

28. Small Molecules and Ions as Second Messengers • First messengers are the extracellular signal molecule that binds to the membrane receptor • Not all components of signal transduction pathways are proteins • Second messengers are essential to the function of the cascade, transmits the signal from the PM to the metabolic machinery in the cytoplasm • Are small, nonprotein, water-soluble molecules or ions • readily spread throughout the cell via diffusion • Examples: • cyclic AMP • cyclic GMP • calcium ions and IP3

29. 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 (cAMP) • Epinephrine somehow causes glycogen breakdown without passing through the PM (Southerland) • Epinephrine (adrenaline) binds to a receptor on the PM on a liver cell elevating the concentration of cAMP inside the cell, activating adenylyl cyclase • adenylyl cyclase in PM converts ATP into lots of cAMP • cAMP carries the signal into the interior of the cell where it initiates glycogen breakdown • cAMP does not last if epinephrine is not present because of phosphodiesterase (turns cAMP into AMP) • more epinephrine is needed to boost amount of cAMP in cytosol • cAMP activates protein kinase A which causes a cellular response

30. Many G-proteins • Trigger the formation of cAMP, which then acts as a second messenger in cellular pathways video Figure 11.10

31. 11.4 Response • Concept 11.4: Cell signaling leads to regulation of cytoplasmic activities or transcription

32. 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 and Nuclear Responses • In the cytoplasm • Signaling pathways regulate a variety of cellular activities • regulating the activity of the enzyme • Epinephrine • In the nucleus • Synthesis of mRNA (transcription)

33. Epinephrine • Same receptor • Different response • inhibition or promotion of glycogen

34. Kidneys Adrenal gland releases adrenaline (epinephrine) Circulatory system hypothalamus Liver Lungs Intestines Heart

35. Growth factor Reception Receptor Hormone (testosterone) EXTRACELLULAR FLUID Phosphorylation cascade Transduction Plasma membrane Receptor protein Hormone- receptor complex CYTOPLASM Inactive transcription factor Active transcription factor DNA Response P mRNA DNA Gene NUCLEUS New protein mRNA NUCLEUS CYTOPLASM Figure 11.6 Figure 11.14 Other pathways • Regulate genes by activating transcription factors that turn genes on or off • regulate the synthesis of enzymes or proteins, unlike epinephrine

36. Fine-Tuning of the Response • Signal pathways with multiple steps • Can amplify the signal and contribute to the specificity of the response • Signals can be fine tuned in several way • Signal Amplification • Specificity • Efficiency • Termination

37. 1) Signal Amplification • Each protein in a signaling pathway • Amplifies the signal by activating multiple copies of the next component in the pathway • Epinephrine triggered pathways: each adenylyl cyclase catalytic event forms more cAMP molecules and each protein kinase phosphorylation makes more of the next kinase; thus amplifying all the products in transduction making hundreds of millions of glucose molecules from glycogen

38. Signalmolecule Receptor Relaymolecules Cell B. Pathway branches, leading to two responses Cell A. Pathway leads to a single response Response 2 Response 1 Response 3 Activationor inhibition Cell D. Different receptor leads to a different response Cell C. Cross-talk occurs between two pathways Response 4 Response 5 Figure 11.15 2) The Specificity of Cell Signaling • The different combinations of proteins in a cell • Give the cell great specificity in both the signals it detects and the responses it carries out • Pathway branching and “cross-talk” • Further help the cell coordinate incoming signals

39. Signalmolecule Plasmamembrane Receptor Threedifferentproteinkinases Scaffoldingprotein Figure 11.16 3) Signaling Efficiency • Scaffolding proteins (large relay proteins to which several other relay proteins are simultaneously attached) • Can increase the signal transduction efficiency by participating in several pathways

40. 4) Termination of the Signal • Signal response is terminated quickly • By the reversal of ligand binding • Active and inactive forms on the receptor • cAMP to AMP

41. Real Applications • Fight or Flight