caffeine

1. Signaling via Ligand-Receptor Binding Agonist - ligand binding to a receptor and eliciting a response caffeine Antagonist - ligand binding to a receptor but not eliciting a response Brain sleep signal R + L ↔ R∙L Kd = [R][L]/[R∙L]

2. Bacterial Quorum Sensing Increased cell density dependant signaling Activation of Bio-film formation which affects bacterial resistance

3. Extracellular Signals

4. Signal Transduction Cascade What is effective signaling? Specificity? Sensitivity?

5. Common Second Messengers Source of these metabolites?

6. Seven-Transmembrane-Helix Receptors Biological functions mediated by 7TM receptors

7. G-Protein Pathway Activation by Epinephrine Beta-adrenergic receptors stimulate glycogenolysis (skeletal muscles) and gluconeogenesis (liver); blood flow to those muscles.

8. External Signal for G-Protein Activation β2-adreneric receptor

9. Heterotrimeric G Protein α, β, and γ subunits (blue, green, and yellow, respectively) associated with GDP (orange) Side view Cartoon side view Top view

10. Adenylate Cyclase Activation/Deactivation What does adenylate cyclase catalyze?

11. Generation of Cyclic AMP How is adenylate cyclase activated? How are G proteins reset?

12. Protein Kinase A Activation by cAMP How is cyclic AMP deactivated/turned off?

13. Cyclic AMP Deactivation How is the primary signal for G-protein signaling reset?

14. Protein Kinase A Regulation by Phosphorylation Dephosphorylation blocks substrate from active site Catalytic subunit: light green Activation loop: dark green Substrate target protein: blue

15. Ligand Dissociation and Signal Termination Ligand-receptor interaction is reversible What is the basis of the receptor being in the ligand-bound or unbound state?

16. Cholera Causes Altered G-Protein Signaling Intestinal bacterium Vibro cholera produces a protein cholera toxin B-subunit enters the cell and covalently modifies Gα trapping it in the active form Protein kinase A opens a chloride channel and inhibits a Na+-H+ exchanger Effect loss of NaCl and water Disfunctional G-protein signaling can be lethal

17. G-Protein Pathway Activation by Epinephrine Alternative second messengers?

18. Alternative Second Messenger with G-Protein Activation α-Adreneric receptor is also activated by epinephrine and norepinephrine. Smooth muscle contraction (e.g. skin and kidney). IP3, a product of phosphatidylinositol bisphosphate hydrolysis signals a calcium influx and protein kinase C activation

19. Phosphoinositide Cascade

20. Calcium Binding Protein: Calmodulin Ca+2 ions EF-hand protein family: helix-loop-helix Extended unbound form Bent bound to a target protein

21. Phosphinositide Signaling System

22. Alternative to 7TM Receptors Receptor tyrosine kinases that dimerize with ligand binding Recruit tyrosine kinases with ligand binding and dimerization

23. Receptor Tyrosine Kinases Ligand binding allows the receptor monomer to form a dimer unit with cytoplasmic kinase domain catalytically active

24. Insulin Receptor Tyrosine Kinase Activation Inactive form (blue) Activation loop (dark blue) Active form (green) Activation loop (dark green) Note: Activation loop swings out with Tyr phosphorylation

25. Receptor Tyrosine Kinases Operative for certain hormones and signaling molecules that regulate growth (e.g. insulin, growth factors)

26. Ras Superfamily of GTPases

27. Insulin Transduction Sequence Net effect: increases glucose uptake by cells and conversion of glucose to glycogen.

28. Phosphatidylinositide-3-kinase Catalysis

29. Insulin Signaling Pathway Insulin receptor substrates (IRS) Akt also known as protein kinase B

30. Chapter 13 Problems: 2-12