1. 02.07.11 Lecture 9: Cell Communication I

2. Multicellular organisms need to coordinate cellular functions in different tissues Cell-to-cell communication is also used by single celled organisms to signal to other organisms Biologists have discovered several universal mechanisms of cellular regulation

3. General mechanism of cellular signaling 1. Reception of signal 2. Transduction of signal 3. Cellular response

4. Signal transduction Conversion of information from one form into another

5. Signaling cascades perform 5 crucial functions 1.Transduce signal into molecular form that can stimulate response Relay signal from point of reception to point of action in the cell Amplify the received signal Distribute the signal to influence several responses in parallel Each step is open to modulation by other signals

6. Receptors relay signals via intracellular signaling pathways Individual cells respond to a limited set of signals for which they have receptors A single cell may have 10 to 100,000 different receptors Many signals acting together can elicit different cellular responses - a complex network

7. A signaling molecule may induce different responses in different cell types

8. Extracellular signals can act slowly or rapidly

9. Signaling via chemical signals: direct communication

10. Signaling via chemical signals: local communication

11. Signaling via chemical signals: long-range communication

12. Extracellular signaling molecules fall into 2 classes: 1. Molecules that are small enough or hydrophobic and pass through the membrane - directly activate intracellular receptors in the cytoplasm or nucleus of target cell 2. Molecules that are too large or too hydrophilic to cross the plasma membrane - rely on membrane receptors

13. Nitric oxide (NO) signals through a cytoplasmic receptor NO is a chemically unstable gas NO is a small, uncharged molecule

14. Steroid hormones signal through intracellular receptors Steroid hormones are structurally similar to cholesterol Hydrophobic

15. Cell surface receptors fall into 3 main classes

16. 1. Ion-channel-linked receptors Convert chemical signals ==> electrical signals

17. 2. G-protein-coupled receptors Largest family of cell surface receptors 7 transmembrane  -helices Extracellular N-term, intracellular C-term C-terminus interacts with downstream effectors

18. Many signaling proteins act as molecular “switches”

19. G proteins dissociate into 2 signaling complexes when activated 1. Signal molecule binds GPCR 2. Activated GPCR induces exchange of GDP for GTP on G  subunit 3. G  dissociates from G  4. Activated subunits diffuse within the plane of the membrane to activate downstream signaling molecules

20. The G  subunit inactivates itself by hydrolyzing its GTP

21. G proteins regulate 2 types of targets 1. Ion channel opening (I.e. K+channels in heart muscle cells) 2. Membrane-bound enzymes (e.g. adenylyl cyclase, phospholipases)

22. Some G proteins regulate ion channels Acetylcholine slows the heart Receptor activation ==> dissociation of G  and G  G  opens K+ channels to decrease the amplitude of contraction

23. Some G proteins regulate membrane- bound enzymes to make second messengers

24. Two most common enzymes activated by G proteins Adenylyl cyclase - converts ATP into cyclic AMP (cAMP) Phospholipase C - cleaves a lipid (isositol phospholipid) into isositol-1,4,5-trisphosphate (IP 3, a hydrophilic sugar) and diacylglycerol (DAG, a lipid in the membrane)

25. Cyclic AMP (cAMP) is a common second messenger cAMP is generated from ATP by adenylyl cyclase cAMP is degraded by cAMP phosphodiesterase Caffeine inhibits phosphodiesterase cAMP activates cAMP- dependent protein kinase (PKA)

26. The activation of cyclic-AMP - dependent protein kinase (PKA)

27. Intracellular cAMP can activate gene transcription

28. Calcium ion concentrations are kept low in the cytosol by calcium pumps

29. Phospholipase C activates 2 signaling pathways