1. The document discusses characterizing G protein-coupled receptor signaling and regulation by kinases in differentiated cell functions and disease. 2. It provides examples of how arrestins can desensitize beta-2 adrenergic receptors in airway smooth muscle cells and impact tissue and organ function. 3. Questions are raised about the roles of various G protein-coupled receptors in cancer cell growth and survival and how inflammation, stress, and anti-inflammatory agents may impact these processes through cyclic AMP signaling.

2. Example: Arrestins desensitize  2 ARs in ASM to mitigate relaxant effect of beta-agonists

3. GPCR Regulation

4. β arr2-KO Targeting arrestins increases ASM  2 AR signaling in ASM cells Murine: Human:

5. Tissue function: airway relaxation ex vivo

6. Organ system function

9. Antiapoptotic effects of epinephrine and forskolin depend on PKA activation Sastry, K. S. R. et al. J. Biol. Chem. 2007;282:14094-14100 LNCaP cells

10. 1. Can other G s -coupled receptors: EP2 prostaglandin IP prostacyclin A2a or A2b adenosine GPR4 proton-sensing similarly regulate cancer cell survival? 2. What are effects of: a. Stress (increased circulating EPI/NE); b. Inflammation and anti-inflammatory agents NSAIDS and Glucocorticoids ( ↓ inflammatory prostanoids) Questions:

13. EPITHELIAL CELLS FIRST HIT PRE- MALIGNANT CELLS

14. STEM CELLS PRE- MALIGNANT CELLS STROMAL CELLS STEM CELLS INFLAMM BLOOD CELLS + + ? ? + TUMOR CELLS STROMAL CELLS +

17. TUMOR CELLS STROMAL CELLS STEM CELLS INFLAMM BLOOD CELLS

21. Example 2: PKC desensitizes the CysLT1R to alter LTD4-regulated ASM and monocyte function

22. Human Cysteinyl Leukotriene CysLT1 Receptor PKC PKC PKC PKC PKA PKA PKA C C C C A A A

23. A B C D E F Fig. 7

24. A B C D E STRUCTURE-FUNCTION APPROACH: RECEPTOR SIGNALING, TRAFFICKING

25. Fresh Human Monocytes THP-1 Monocyte cell functions

26. Airways ex vivo CysLT1R m3mAChR

27. A B C D