1. Cell to Cell Communication
Chapter 11
Universal mechanisms for cell regulation = evidence of evolution
Viagra – inhibits enzyme that shuts down dilation of vessels

2. Example of Cell to Cell Communication
Yeast’s version of sex
Two types of cells (a and )
Each secretes a mating factor that binds to receptor on opposite cell
Binding of mating factors lead to cell growth and fusion
Nucleus of fused cell contains DNA from both a and .
Signal pathways of yeast and mammals very similar even the most recent common ancestor lived over 1 billion years ago
Early cell signals evolved before multicellular organisms

3. Figure Yeast

4. Figure 11.1 Communication between mating yeast cells

5. Local and Long Distance Signaling
Local signaling – influences cells in the nearby vicinity
Paracrine signaling – secreting cell releases a regulator in the the extracellular matrix
Synaptic signaling – nerve cell releases neurotransmitter into a synapse (space between nerves)
Long Distance signaling – can influence cells all over body
Hormone signaling – endocrine cells secrete hormones into blood where they can reach any cell
Paracrine example – growth factors that stimulate cell growth
Hormones
Ethylene gas ripens fruit (one bad apple spoils the bunch)
Insulin – regulates blood sugar

6. Figure 11.3 Local and long-distance cell communication in animals

7. Figure 11.4 Communication by direct contact between cells
Cell junctions and cell-cell recognition

8. Three Stages of Cell Signaling
Reception – target cell’s detection of a chemical signal
Signal is detected when it binds to a receptor
Ligand – a signal molecule that binds to a receptor
Transduction – binding of signal to receptor stimulates a change in the receptor.
The changed receptor triggers a step or many steps that lead to the cell response.
Response – end result – the cell response
Earl Sutherland (Nobel prize in 1971) investigated epinephrine
Glycogen in liver broken down releases glucose-1-phosphate
glucose-1-phosphate converted to glucose-6-phosphate or just glucose for use in glycolysis
Epinephrine stimulates the break down of glycogen so it mobilizes fuel reserves in times of stress or fear
Epinephrine stimulates glycogen phosporyllase to do this, but does not come into contact with it directly
Put Epinephrine and glycogen phosporyllase and glycogen in a test tube and no break down!

9. Figure 11.5 Overview of cell signaling (Layer 1)

10. Figure 11.5 Overview of cell signaling (Layer 2)

11. Figure 11.5 Overview of cell signaling (Layer 3)

12. Receptors
Intracellular receptors – found in cytoplasm or on nucleus so signal must pass through cell membrane first
Ex. NO and steroid hormones like testosterone
Testosterone receptor only found in certain cells
An activated testosterone receptor acts as a transcription factor
Transcription factors - turn on or turn off genes

13. Figure 11.10 Steroid hormone interacting with an intracellular receptor

14. Cell Membrane Receptors – found in cell membrane
Three major types
G-linked receptor
Receptor tyrosine kinase
Ligand-gated ion channel

15. Figure 11.6 The structure of a G-protein-linked receptor

16. Figure 11.7 The functioning of a G-protein-linked receptor
GDP on G protein – inactive
When receptor activated, binds to inactive G protein and GDP is displaced by GTP
Activated G protein leaves and binds to an enzyme to stimulate pathway
G protein soon hydrolyzes GTP into GDP and makes itself inactive
Cholera, pertussis (whooping cough), botulism all from bacterial toxins that interfere with G protein
Pharmacists realize that up to 60% of all medicines used today exert their effects by influencing the G protein pathways

17. Figure 11.8 The structure and function of a tyrosine-kinase receptor
Binding of signal causes 2 receptors to associate closely (dimerization)
This activated the tyrosine regions and each adds a P from ATP
Inactive relay proteins can now bind to the receptor and trigger pathway
One single ligand binding event can trigger multiple pathways bcz of multiple phosphorylated tyrosines
Abnormal tyrosine kinases that dimerize when they shouldn’t may be involved in some kinds of cancer

18. Figure 11.9 A ligand-gated ion-channel receptor
Signal binding opens gate which allows ions to flow thru protein.
Very important in nervous system
Some gates controlled by electrical signals instead of chemical ligands.

19. Often involves protein phosphorylation and dephosphorylation
Transduction
Signal transduction pathways – a chain of molecular interactions (like falling dominoes)
Often involves protein phosphorylation and dephosphorylation
Protein kinases – enzymes that transfer phosphate groups from ATP to a protein
Phosphorylation of protein often changes protein from inactive to active form
Protein phosphatases – enzymes that rapidly remove P (often turn off pathway)
Conformational changes in each chemical intermediate (shape changes)
About 2% of genes code for protein kinases

20. Figure 11.11 A phosphorylation cascade

21. Second Messengers
Second messengers – small, nonprotein, water-soluble molecules or ions that are part of signaling pathways
Two most common second messengers
Ca2+
Cyclic adenosine monophosphate (cAMP or cyclic AMP)

22. cAMP
Adenylyl cyclase – an enzyme in cell membranes that converts ATP into cAMP
Phosphodiesterase – an enzyme that converts cAMP into AMP

23. Figure Cyclic AMP

24. Figure 11-12x cAMP

25. Figure 11.13 cAMP as a second messenger
Epinephrine binding to G protein activates adenylyl cyclase
Adenylyl cyclase makes cAMP from ATP and begins pathway
Cholera (Vibrio chlorae) from drinking water contaminated with human feces
Cholera toxin is an enzyme that modifies the G protein which regulates salt and water secretion
The modified G protein remains stuck in its active form, continuously stimulating adenylyl cyclase to make cAMP
High cAMP causes intestinal cells to secrete large amounts of water and salts… diarrhea
Without treatment, death can occur in hours
With treatment, less then 1% die
Treatment (sugar and salt mixed with water)
Viagra – inhibits hydrolysis of cGMP to GMP, thus prolonging signal and increases blood flow (first used as medicine for heart)

26. Ca2+
Second messenger involved in growth factors, some hormones, muscle contractions, neurotransmitters, and cell division
Ca2+ levels are high in the blood, ER, and sometimes mitochondria and chloroplasts
Low Ca2+ cytosol concentration allows even small fluctuations to trigger pathways

27. Figure 11.14 The maintenance of calcium ion concentrations in an animal cell

28. Figure 11.15 Calcium and inositol triphosphate in signaling pathways (Layer 1)
PIP 2 is cleaved into IP3 inositol triphosphate and DAG (diacylglycerol).

29. Figure 11.15 Calcium and inositol triphosphate in signaling pathways (Layer 2)
IP3 stimulates Ca2+ channel to release Ca2+ into cytoplasm

30. Figure 11.15 Calcium and inositol triphosphate in signaling pathways (Layer 3)
IP3 (inositol triphosphate) can be cleaved to activate Ca2+ release

31. Figure 11.16 Cytoplasmic response to a signal: the stimulation of glycogen breakdown by epinephrine

32. Figure 11.17 Nuclear response to a signal: the activation of a specific gene by a growth factor

33. Fine Tuning of Response
Signal Amplification – number of activated products is much greater than in preceding step
Specificity – different cells have different proteins so two cells can respond to same signal in different manner
Ex. epinephrine stimulates liver to break down glycogen and heart cells to contract faster
Scaffolding Proteins – large relay proteins to which several other relay proteins are attached

34. Figure 11.18 The specificity of cell signaling

35. Figure 11.19 A scaffolding protein
Wiskott-Aldrich syndrome (WAS) – inherited disease (sex-linked)
Incidence is 4 cases per 1 million live male births
Absence of signal relay proteins leads to abnormal bleeding, eczema, increased infections, and leukemia
WAS proteins seem to function as a bridge between signaling and movement of the actin filaments in the cytoskeleton
Median survival has increased from 8 months (patients born before 1935) to longer than 6 years (patients born after 1964).20 In one recent case series, 94 surviving patients ranged in age from 1-35 years, with a median of 11 years; the average age of patients who died was 8 years

36. Apoptosis Apoptosis - triggered by signals that activate cell suicide
In C. elegans (small worm), death genes called ced. When activated they stimulate death by activating proteases and nucleases.
Very similar genes found in other animals including humans
Apoptosis problems are associated with cancer, Parkinson’s, and alzheimer’s
Faulty Ced-4 genes associated with melanoma in humans.
Webbed digits from faulty apoptosis as well as Alzheimers and Parkinsons.