1. No cell lives in isolation Survival depends on an elaborate intercellular communication network Need to coordinate growth, differentiation and metabolism Cells adjacent to one another need to communicate through cell-cell contact Cells distant to each other need to use extracellular signaling molecules

2. OVERVIEW What are Signals? How do cells “pick up” these signals How is the signal passed from the outside of the cell to the inside? How Do Signal Receptors start a Cellular Response? How Is the Response to a Signal transduced (transmitted) through the Cell? What types of responses to signal do cells make? How Do Cells Communicate Directly?

3. What Message If the fire alarm sounded and a real fire blazed through the biology lab at this very moment How would you respond Physically? Externally Chemically? Internally?

4. SUMMARY of the Process Signaling molecules are released by signaling cells Signal is called the ligand Ligand binds to its specific receptor on a target cell Ligand-receptor interaction causes a conformational shape-change in the receptor effectively passing the message to the inside of the cell The signal is transmitted to multiple locations and compound in the cell This cells produces a specific and appropriate response - the cellular response in the cell

5. What is a Signal? All cells process information from their environment. The information can be an external physical stimulus such as light, sound, heat, pressure or an internal chemical signal Examples of these include some proteins, and steroid based hormones All signal transduction pathways involves a signal, a receptor, and a response that can vary from cell to cell.

6. Analogy Short or long distance? Is target general or specific? You want to tell a friend across the room about a party, but you don’t want anyone else in class to know about it. How do you get this message to them before class is over? A teacher wants to remind the class that they have a test. What’s the best way to contact every student? A counselor at high school needs to give an application to all the seniors who are applying for admission. How can you tell each of these people?

7. Basic Events in a Signal Transduction Pathway

8. Circulating & Local Hormones Circulating hormones –act on distant targets –travel in blood –endocrine hormones Local hormones –paracrine hormones (adjacent) –autocrine hormones (self)

9. Lipid-soluble Hormones Steroid Hormones –Mechanism of action is to alter gene expression –Effects tend to be less dramatic but more sustained –lipids made from cholesterol in SER –functional groups provide uniqueness Testosterone –the active hormone receptor complex enters nucleus & binds to specific genes causing increased or decreased transcription depending on the gene Thyroid hormones –Similar to testosterone except receptor protein is IN nucleus –activate enzymes involved in the catabolism of fats and glucose –help set our basal metabolic rate

10. Water-soluble Hormones Small peptides and protein hormones –serotonin, melatonin, histamine, epinephrine –larger peptide hormones insulin and glucagon –Protein Hormones generally activate biochemical pathways and enzymes in cytoplasm but can also have effects at the gene level affecting transcription –Effect tends to be dramatic but short lived

11. Two Possible Locations for Receptors: Membrane bound or Cytoplasmic

12. Examples of Membrane Bound Signal Receptors Ion channels: Ligand binding changes the confirmation of the receptor so that specific ions flow through it This ion movement alters the electric potential across the plasma membrane –found on the plasma membrane of muscle cells –ligand-gated channels for Na + and K + found on neurons

13. A Gated Ion Channel

14. Direct and Indirect Signal Transduction Direct signal transduction occurs at plasma membrane and is a function of the receptor itself. The signal is considered the first messenger. Example – Gated Ion Channels Indirect signal transduction: Another molecule—the second messenger—mediates interaction between receptor and cell’s response. The second messenger is released into the cytoplasm after signal binds to receptor. –Second messengers can affect many processes in the cell. –They can amplify signals –G Protein and Tyrosine Kinase Pathways often involve second messengers

15. Direct Signal Transduction

16. Indirect Signal Transduction

17. cAMP – an example of a second messenger cAMP is a common second messenger. cAMP has two major target types: Binds to ion channels in many kinds of sensory cells and opens the channel Binds to protein kinases in cytoplasm –this exposes the active site and starts a protein kinase cascade Another example of a second messenger is calcium –Calcium channels exist on the plasma membrane of the ER – A release of calcium in pancreatic beta cells triggers the export of insulin –a rise in intracellular calcium also triggers contraction of muscle cells

18. Examples of Membrane Bound Signal Receptors G protein-linked receptors: They are activated by directly binding to GTPG protein-linked receptors 60% of medicinal drugs target this signal pathway. Used by many signal molecules; yeast mating factors, epinephrine, and other hormones and neurotransmitters Involved in transmission of vision, mood, smell and many more Also can cause the release of second messenger molecules such as cAMP and Ca 2 + ions Extremely diverse and widespread in function but have lots of similarities between organisms which indicates they evolved very early

19. Action of a G Protein-Linked Receptor

21. Our Sense of Smell: A Signal Transduction Pathway Smell involves two signal transduction pathways A G protein molecule initiates a pathway resulting in the activation of an Ion Channel Odorant molecules bind to receptors in the nose This activates a G protein This activates adenylyl cyclase which catalyze’s the formation of cAMP, which opens ion channels. Influx of Na + and Ca 2+ through the ion channels is a key step in the initiation of an action potential – a nerve impulse Nerve sends signals to the brain. We respond - “Who farted”?

22. How we recognize and respond to smell

23. Odor triggers the opening of an Ion Channel

24. Examples of Membrane Bound Signal Receptors Protein kinase receptors: Binding of Ligand triggers formation of dimer Dimer activates a class of proteins called Tyrosine Kinase’s Tyrosine Kinase’s phosphorylate downstream targets Can trigger more than ONE signal transduction pathway at once. Can cause the release of second messenger molecules such as cAMP and Ca 2 + ions Second Messengers go on to active a variety of different proteins resulting in many different cellular responses These pathways often result in amplification of the signal Insulin Pathway – Insulin is a pancreatic hormone involved in glucose regulation

25. A Protein Kinase Receptor – Ex. Insulin

26. A G Protein Initiated Pathway resulting in a Protein Kinase Cascade and Amplification of the Signal Liver cells can be stimulated by epinephrine (adrenaline) Triggers a G protein stimulated Protein Kinase Cascade This results in two enzymes being phosphorylated Glycogen synthase is inhibited –this prevents glucose from being stored as glycogen Phosphorylase kinase is activated stimulates a cascade that activates glycogen phosphorylase which catalyzes conversion of glycogen to glucose Both events give more glucose for “flight or fight” response. –One mol of epinephrine results in 10,000 mol’s of glucose.

29. Examples of Signal Transduction Pathway in Bacteria Differential gene transcription in response to an environmental change in Bacteria Ex. EnvZ example

30. Gene Regulation Example: How does E.coli respond to a change in solute concentration? The solute concentration around E. coli in a mammalian intestine changes often. The bacterium must respond quickly to this environmental signal or face death.

31. Description of the process The E. coli receptor for solute concentration is EnvZ, a transmembrane protein in the plasma membrane. Solute “signal” binds to EnvZ causes a change in the conformational shape of this receptor protein. This shape change exposes an active site, and EnvZ phosphorylates (energizes) itself (using ATP). –Proteins that can phosphorylate themselves or other proteins are called “protein kinase’s” EnvZ acting as a protein kinase now binds briefly to another protein – OmpR, and transfers a phosphate The shape of OmpR changes

32. Description of the process Thus the outside signal from has been transduced (transferred) to a protein inside the cell. Effect: Phosphorylated OmpR binds to DNA to cause an increase in the amount of OmpC produced The OmpC protein is inserted in the outer membrane where it blocks pores and prevents solutes from entering. This is the CELLS RESPONSE. Note: The signal has also been amplified –One EnvZ molecule can change the conformation of MANY OmpR molecules. –Each OmpR molecule can cause the production of MANY OmpC proteins

33. A Model Signal Transduction Pathway - Overview Note: You are looking at the structure of a bacterial cell

34. The Purpose of Protein Kinase Cascades “Information” that arrives at the membrane can be communicated to the nucleus At each step the signal can be amplified Each step in the cascade allows for specificity of response –different target proteins provide a variety of different responses – intra cellular, extra cellular and at the DNA level

35. Interaction of Different Signaling Pathways The same cell response may be caused by many signaling pathways using different mechanisms This Interaction of different signaling pathways permits fine- tuning of cellular activities - crosstalk

36. Animal Cell Communication: Gap Junctions These are Channels between adjacent cells made of proteins called connexons – allows for co-operation Too small for proteins, but wide enough for signaling molecules such as cAMP, calcium, ATP, Amino acids, coenzymes etc The gaps can open and close in response to ion concentrations thereby controlling flow of ions –Lens cells of mammalian eyes have many gap junctions as only the cells at the outside are close to blood vessels. –Only a few cells would need to have signal receptors, the signal could spread through entire tissue for a coordinated response.

37. Animal Cell Communication: Gap Junctions

38. Plant Cells: Plasmodesmata Plant cells have 1000’s of plasmodesmata in the cell walls. Lining is made of fused plasma membranes from both cells. A tubule, the desmotubule, ( from the ER ) fills the channel. Plants rely on the rapid diffusion of hormones through plasmodesmata to ensure that all cells respond to a signal at the same time. Some larger molecules and particles can pass through plasmodesmata. Plant viruses can move through plasmodesmata by making “movement proteins” to assist their passage

39. Plant Cells: Plasmodesmata