CELL COMMUNICATION & SIGNAL TRANSDUCTION

1. CELL COMMUNICATION & SIGNAL TRANSDUCTION Angelica D Francisco, MD, MSc

2. FUNCTIONAL INTEGRATION OF ORGAN SYSTEMS • CARDIOVASCULAR SYSTEM • RESPIRATORY SYSTEM • RENAL SYSTEM • GASTROINTESTINAL SYSTEM • BLOOD & IMMUNE SYSTEM • NERVOUS SYSTEM • ENDOCRINE SYSTEM • MUSCULAR SYSTEM • REPRODUCTIVE SYSTEM

3. OBJECTIVES • EXPLAIN THE IMPORTANCE OF INTERCELLULAR COMMUNICATION HOMEOSTASIS. • ENUMERATE & DESCRIBE THE TYPES OF INTERCELLULAR COMMUNICATION. • DESCRIBE THE TYPES OF RECEPTORS AND THE THEIR EFFECTS ON THE CELL IN RESPONSE TO CHEMICAL SIGNALS.

4. OBJECTIVES • DESCRIBE THE DIFFERENT SIGNAL TRANSDUCTION MECHANISMS IN THE CELL. • DESCRIBE THE EVENTS IN RESPONSE TO STMULATION OF G-PROTEIN COUPLED RECEPTORS. • EXPLAIN THE FUNCTION OF SECOND MESSENGERS IN THE TRANSDUCTION OF CHEMICAL SIGNALS IN THE CELL.

5. CELL COMMUNICATION • THE MECHANISM FOR THE CONTROL AND COORDINATION OF CELL RESPONSE

6. CHEMICAL MEDIATORS & RECEPTORS CHEMICAL MESSENGERS • HORMONES • NEUROTRANSMITTERS • OTHERS: AMINES, AMINO ACIDS, POLYPEPTIDES, NUCLEOTIDES

7. CHEMICAL MEDIATORS & RECEPTORS RECEPTORS • PROTEIN MOLECULES TO WHICH A CHEMICAL MESSENGER CAN BIND IN ORDER TO STIMULATE A CELL RESPONSE • FOUND IN CELL MEMBRANE, CYTOPLASM, NUCLEUS

8. TYPES OF INTERCELLULAR COMMUNICATION • NEURAL COMMUNICATION via NEURONS • ENDOCRINE COMMUNICATION via BLOOD/LYMPH • PARACRINE/AUTOCRINE via ECF

9. INTERCELLULAR COMMUNICATION

10. GAP JUNCTIONS

11. GAP JUNCTIONS INTERCELLULAR CONNECTION THAT ALLOWS FOR SUBSTANCES TO PASS FREELY BETWEEN CELLS WITHOUT ENTERING THE ECF FUNCTION: • RAPID PROPAGATION OF ELECTRICAL ACTIVITY FROM CELL TO CELL FOUND IN: • CARDIAC MUSCLE • SMOOTH MUSCLE

12. NEURAL COMMUNICATION • RELEASE OF NEUROTRANSMITTER AT SYNAPSE • RAPID COMMUNICATION, msec • LONG DISTANCES • DISCRETE

13. ENDOCRINE COMMUNICATION • RELEASE OF HORMONE INTO BLOOD/LYMPH, AFFECTING DISTANT TARGET CELL • EFFECT SLOW (sec to hrs) • EFFECTS PROLONGED • DISCRETE (eg. ANTIDIURETIC HORMONE) OR DIFFUSE (eg. INSULIN, THYROID HORMONE)

14. PARACRINE COMMUNICATION PARACRINE • SECRETION OF CHEMICAL INTO IF, ACTS ON NEARBY CELLS

15. AUTOCRINE COMMUNICATION AUTOCRINE • SECRETION OF CHEMICAL INTO INTERSTITIAL FLUID, AFFECTING SAME CELL

16. RECOGNITION TRANSMITTER-RECEPTOR BINDING • TRANSDUCTION SECOND MESSENGER eg. cAMP • TRANSMISSION SECOND MESSENGER SIGNAL TO EFFECTOR • RESPONSE

17. RECOGNITION RECEPTOR:LIGAND BINDING

18. RECEPTORS FOR CHEMICAL MESSENGERS REGULATION OF RECEPTORS • UP-REGULATION: INCREASE IN NUMBER WHEN CHEMICAL MESSERNGER IS DEFICIENT

19. RECEPTORS FOR CHEMICAL MESSENGERS REGULATION OF RECEPTORS • DOWN-REGULATION: DECREASE IN NUMBER/ACTIVITY WHEN CHEMICAL MESSENGER IS IN EXCESS INTERNALIZATION (DECLINE IN NUMBER) DESENSITIZATION (LESS RESPONSIVE)

20. SIGNAL TRANSDUCTION mechanisms types • ION CHANNEL ACTIVATION • G-PROTEIN ACTIVATION • ACTIVATION OF ENZYME ACTIVITY IN THE CELL • DIRECT ACTIVATION OF PROTEIN TRANSCRIPTION

21. SIGNAL TRANSDUCTION • FIRST MESSENGER: EXTRACELLULAR LIGANDS • SECOND MESSENGER: INTRACELLULAR MEDIATORS AMPLIFIES RESPONSE

22. TYPES OF RECEPTORS Cell membrane receptors • ION CHANNEL-LINKED RECEPTORS • G-PROTEIN COUPLED RECEPTORS • ENZYME-LINKED/CATALYTIC RECEPTORS Intracellular receptors • NUCLEAR RECEPTORS

23. ION CHANNEL-LINKED RECEPTORS • Action: CHANGE IN ION PERMEABLILITY OF the MEMBRANE

24. LIGAND-GATED ION CHANNEL • Action: INCREASED MEMBRANE PERMEABILITY TO Na+ ACETYLCHOLINE GATED Na+ CHANNEL

25. G-PROTEIN COUPLED RECEPTORS RECEPTORS ARE INTEGRAL PROTEINS WHOSE ACTIVITY IS THROUGH AN INTERMEDIARY G-PROTEIN

26. G-PROTEIN COUPLED RECEPTORS acTION: ACTIVATE/INACTIVATE MEMBRANE ASSOCIATED ENZYMES OR CHANNELS

27. G-PROTEIN COUPLED RECEPTOR SEVEN-HELIX RECEPTORS “SERPENTINE RECEPTORS”

28. G-PROTEIN COUPLED RECEPTOR • 3 SUBUNUITS • -SUBUNIT: BOUND TO GDP (INACTIVE) • β-SUBUNIT • γ-SUBUNIT • α AND γ-SUBUNITS ARE ATTACHED TO MEMBRANE GDP, GUANOSINE DIPHOSPHATE

29. GPCR SIGNALING

30. GPCR SIGNALING GEF, GUANINE EXCHANGE FACTORS

31. GPCR SIGNALING

32. GPCR SIGNALING

33. GPCR SIGNALING

34. GPCR SIGNALING GRS, REGULATOR OF G-PROTEIN SIGNALING

35. GPCR SIGNALING • ACTIVATION BY RECEPTOR-LIGAND BINDING • RECEPTOR INTERACTS WITH G-PROTEIN: GDP GTP • G-PROTEIN DISSOCIATES FROM RECEPTOR

36. GPCR SIGNALING • α-GTP AND βγ SUBUNITS DISSOCIATE • BOTH α-GTP AND βγ SUBUNITS INTERACT WITH THEIR EFFECTORS • HYDROLYSIS OF GTP TO GDP INACTIVATES α-SUBUNIT  REASSEMBLY OF TRIMER

37. GPCR TRANSDUCTION PATHWAY • ACTIVATION/INIBITION OF ADENYLYL CYCLASE: ATP  cAMP (Gs/Gi)

38. GCPR SECOND MESSENGER: cAMP aCTION: ACTIVATION OF PROTEIN KINASE A, PKA  • CATALYZE PHOSPHORYLATION OF PROTEINS (i.e.,STIMULATION/INHIBITION OF ENZYMES) • PHOSPHORYLATES CREB IN NUCLEUS (i.e., REGULATE TRANSCRIPTION OF GENES) CREB, cAMP RESPONSIVE ELEMENT BINDING PROTEIN

39. GPCR TRANSDUCTION PATHWAY • Action: ACTIVATION OF PHOSPHODIESTERASE: cGMP GMP

40. GCPR SECOND MESSENGER: cGMP aCTIONs • CLOSURE OF cGMP-REGULATED ION CHANNELS(i.e., ALTERS MEMBRANE PERMEABILITY TO IONS) • ACTIVATES cGMP-DEPENDENT KINASE (i.e., STIMULATION/INHIBITION OF ENZYMES)

42. GPCR TRANSDUCTION PATHWAY Action: activateS PHOSPHOLIPASE C, PLC PIP2 (Phosphatidyl Inositol biPO4) PLC DAG + InsP3

43. GPCR TRANSDUCTION PATHWAY Action: activATES PHOSPHOLIPASE A2 MEMBRANE LIPIDS PLA2 ARACHIDONIC ACID

44. GCPR SECOND MESSENGER: InsP3/DAG actions: • InsP3, INOSITOL TRIPHOSPHATE • MOBILIZATION OF INTRACELLULAR Ca++ • DAG, DIACYLGLYCEROL • ACTIVATES PROTEIN KINASE C, PKC

45. ENZYME-LINKED/CATALYTIC RECEPTORS Ex. Insulin receptor: tyrosine kinase

46. REGULATION OF TRANSCRIPTION

47. NUCLEAR LINKED-RECEPTORS LIGANDS: LIPID SOLUBLE • CYTOPLASMIC RECEPTORS Ex. GLUCOCORTICOIDS & MINERALOCORTICOIDS • NUCLEAR RECEPTORS Ex. ESTROGEN, PROGESTERONE, THYROID HORMONES

48. NUCLEAR RECEPTORS

49. CHOLERA TOXIN

50. CLINICAL APPLICATION ASPIRIN, NON-STEROIDAL ANTI-INFLAMMATORY DRUG • INHIBITS CYCLO-OXYGENASE IN ARACHIDONIC ACID PATHWAY • ANTI-CLOTTING: INHIBITS PLATELET FUNCTION