1. Today: Epinephrine nestles in predicted binding site of predicted human 1- adrenergic receptor. [Proc. Nat. Acad. Sci. USA, 99, 12622 (2002)]. Battery Types Quiz Cell Communication

2. The Basics of Extracellular Cell Signaling

3. Cells can signal themselves (autocrine), nearby cells (paracrine) or distant cells (hormones).

4. A Specific Example…

6. Meet the Ligands… R + L  RL Does this need to be reversible? If so, which direction should be favored? R + L  RL Does this need to be reversible? If so, which direction should be favored?

7. Intracellular and Extracellular Receptors Consider Follicle Stimulating Hormone (FSH), widely used as a fertility drug. Do you expect this hormone to have an intracellular or extracellular receptor? Why? Image: Wadsworth Center, New York State Department of Health

8. Intracellular and Extracellular Receptors Surface and ribbon representation showing the crystal structure of human FSH bound to the extracellular hormone-binding domain of its receptor (FSHR-HB). FSH alpha- and beta-subunits are in green and cyan, respectively. FSHR-HB is in red. A seven-helix transmembrane domain (gray, modeled on the structure of rhodopsin) anchors the receptor in the membrane. Upon receptor binding, FSH undergoes a concerted conformational change that affects the protruding loops, which may in turn play a direct role in activation through the receptor transmembrane domain. (Image: Courtesy Qing Fan and Wayne A. Hendrickson) 2005

9. General Rule

10. 1. Ion Channel Receptors

11. Ion Channel Receptors: Remembering the Sodium Potassium Pump Animation?

12. Ion Channel Receptors

13. You Try! Structure of Acetylcholine (left) and Nicotine (right) Acetylcholine Receptor November 2005 Molecule of the Month by David S. GoodsellMolecule of the Month

14. 2. Protein Kinases: the Insulin Receptor

15. 3. G-Protein Linked (coupled) Receptors- GPCRs Over 60% of all prescription drugs on the market, (12 of the top-20) selling drugs, directly or indirectly target GPCRs (=>$200 billion/yr in sales) Over 60% of all prescription drugs on the market, (12 of the top-20) selling drugs, directly or indirectly target GPCRs (=>$200 billion/yr in sales) Every known GPCR is associated with at least one commercially available drug Every known GPCR is associated with at least one commercially available drug Examples include Zantac® and Pepcid® (ulcers); and morphine (pain) Examples include Zantac® and Pepcid® (ulcers); and morphine (pain) *Bio-Quant, 2001 Epinephrine nestles in predicted binding site of predicted human 1-adrenergic receptor. [Proc. Nat. Acad. Sci. USA, 99, 12622 (2002)].

16. GPCR Mechanism: Overview

17. Another Look at G Protein- Coupled Receptors

18. Cytoplasmic (Intracellular) Receptors

19. Signal Transduction: Direct

20. Signal Transduction: Indirect

21. Signal Transduction: Protein Kinase Cascade Critical Functions: 1.Amplifies Signal 2.Communicates to the Nucleus 3.Multiple steps provides Specificity

22. Example: RAS

23. Second Messengers: Sutherland’s Hypothesis Small, nonprotein, water-soluble molecules/ions that relay a signal Small, nonprotein, water-soluble molecules/ions that relay a signal Rapidly spread a signal through the cell via diffusion Rapidly spread a signal through the cell via diffusion

24. Common Second Messengers: Cyclic AMP (cAMP) cAMP tends to bind to ion channels, opening them, and protein kinases, activating them.

25. Phospholids can be hydrolized to form second messengers Example: Phosphatidyl inositol-bisphosphate (PIP2)

26. Other Common Second Messengers: Ca 2+ A wave of calcium ions spreads through an egg in response to fertilization. Image: http://dept.kent.edu/biology/kline/cawave. htm

27. Other Common Second Messengers: Ca 2+

28. Two or More Second Messengers May Work Together

29. Other Cool Second Messengers: Nitric Oxide “NO news is good news.”

30. Other Cool Second Messengers: Nitric Oxide

32. Viagra…

33. Other Modes: Direct Communication Between Cells