Understanding Cell Signalling Mechanisms: A Comprehensive Overview

1. CELL SIGNALLING D. C. MIKULECKY Dept. Physiology

2. WHAT IS A SIGNAL? • SEMIOTICS • INFORMATION THEORY • NERVOUS SYTEM • ENDOCRINE • PARACRINE • ENDOCRINE • ANTIBODIES AND OTHER FOREIGN SUBSTANCES • PARALLEL PROCESSING

3. CHEMICAL SIGNALS • SIGNALING MOLECULE IS SECRETED • TRAVELS FRON ONE SITE TO ANOTHER • RECEPTOR AT TARGET • BINDING TO RECEPTOR EFFECTS SOME CHANGE

4. ELEMENTS OF CELL SIGNALLING MECHANISMS • SIGNAL MOLECULES • RECEPTORS • SIGNAL TRANSDUCTION

5. SIGNAL MOLECULES (FIRST MESSENGERS) • NEUROTRANSMITTERS • HORMONES • LOCAL MEDIATORS

6. EXAMPLES OF SIGNALLING MOLECULES (SEE TABLE 1 IN TEXT)

7. RECEPTORS • CELL MEMBRANE: HYDROPHILIC SIGNAL MOLECULES (POLYPEPTIDES, CATECHOLAMINES) • CYTOPLASMIC: HYDROPHOBIC SIGNAL MOLECULES (STEROIDS, VITAMIN D, THYROID HORMONE*) *BOUND TO CARRIER PROTEIN

8. LIGANDS, AGONISTS AND ANTAGONISTS • LIGANDS BIND TO RECEPTORS IN A SPECIFIC MANNER • LIGANDS THAT ELICIT A PHYSIOLOGICAL RESPONSE ARE AGONISTS • LIGANDS THAT OCCUPY THE RECEPTOR BUT ELICIT NO RESPONSE ARE ANTAGONISTS (OR “BLOCKERS”)

9. EXAMPLES OF ANTAGONISTS • PROPRANOLOL BLOCKS THE EFFECTS OF CATECHOLAMINES BY BINDING TO THEIR RECEPTORS • SPIRONOLACTONE BLOCKS ALDOSTERONE (DIURETIC)

10. REGULATION OF RECEPTOR QUANTITY AS A CONTROL MECHANISM • DESENSITIZATION BY DOWNREGULATION DUE TO INCREASED ANTAGONIST LEVELS • INTERNALIZATION OF COMPLEX BY ENDOCYTOSIS • RECEPTOR SYNTHESIS (UPREGULATION)

11. AN EXAMPLE OF RECEPTOR RECYCLING

12. MEMBRANE RECEPTORSG-PROTEIN RECEPTOR SUPERFAMILY • MORE THAN 250 MEMBERS • SERPENTINE GLYCOPROTEINS LOOP BACK AND FORTH THROUGH MEMBRANE • EXTRACELLULAR DOMAIN: AMINO TERMINAL PEPTIDE AND THREE LOOPS (HYDROPHILIC REGIONS) • IN THE MEMBRANE:SEVEN ALPHA HELICES OF ABOUT 25 HYDROPHOBIC AA • SEE FIG 8 IN TEXT

13. G-PROTEINS ARE ASSOCIATED WITH THE RECEPTORS • HETEROTRIMERS: , , AND  SUBUNITS • METABOLIC SWITCHES • GTPASE ACTIVITY • BINDING OF LIGAND CAUSES CONFORMATIONAL CHANGE IN  SUBUNIT EXCHANGING GDP FOR GTP • FREE COMPLEX INTERACTS WITH INTRACELLULAR PROTEINS

14. CALCIUM ADENOSINE EPINEPHRINE ANGIOTENSIN ACETYLCHOLINE VASOPRESSIN INTERLEUKIN-8 TSH GLUTAMINE PROSTAGLANDIN E2 SOMATOSTATIN CCK SOME MOLECULES THAT SIGNAL THROUGH G-PROTEIN-COUPLED RECEPTORS

15. SIGNAL TRANSDUCTION AT THE CELL MEMBRANE (SECOND MESSENGERS) INTRACELLULAR SIGNALS (SECOND MESSENGERS) MEMBRANE RECEPTOR LIGAND EFFECT INSIDE CELL (VERY OFTEN THE NUCLEUS)

16. SIGNAL TRANSDUCTION AT THE CELL MEMBRANE (SECOND MESSENGERS) • ADENYL CYCLASE • LIGAND GATED CHANNELS • INOSITAL TRIPHOSPHATE AND DIAGLYCEROL

17. G PROTEINS • INTEGRAL MEMBRANE PROTEIN • COUPLED TO ADENYLATE CYCLASE • Gs STIMULATES • Gi INHIBITS

18. ADENYL CYCLASE A | P | P | P A ADENYLATE CYCLASE + P - P P CYCLIC AMP

19. CYCLIC AMP ACTIVATES PROTEIN KINASES WHICH PHOSPHORYLATE PROTEINS • STRUCTURAL EFFECTS • CALCIUM FLUXES • GENE EXPRESSION • METABOLIC EFFECTS • MEMBRANE EFFECTS

20. SOME HORMONES THAT USE C-AMP AS SECOND MESSENGER • ACTH • EPINEPHRINE • GLUCAGON • LH • PTH • TSH • FSH

21. LIGAND GATED CALCIUM CHANNELS • CONFORMATIONAL CHANGE IN RECEPTOR CAN OPEN CHANNEL • CAN TRIGGER ACTION POTENTIAL OR • PROMOTE CALCIUM TRIGGERED INTRACELLULAR RESPONSE

22. INOSITOL TRIPHOSPHATE AND DIACYLGLYCEROL • BREAKDOWN OF MEMBRANE PHOSPHOLIPID: PHOSPHITYDYLINOSITOL BIPHOSPHATE • SPECIFIC PHOSPHOLIPASE C

23. REMOVAL OF SECOND MESSENGERS FROM THE CYTOSOL • CYCLIC AMP PHOSPHODIESTERASE • CALCIUM PUMPED OUT OF CELL OR INTO SARCOPLASMIC RETICULUM • CALCIUM BINDING PROTEINS

24. PROTEIN KINASES: CONFORMATIONAL CHANGES • SERIES OF PHOSPHORYLATION REACTIONS • EACH KINASE IS SUBSTRATE FOR ANOTHER KINASE • AMPLIFIES SIGNAL 1,000 FOLD

25. PROTEIN KINASES: CONFORMATIONAL CHANGES • UNMASK ACTIVE SITE • UNMASK BINDING SITE PROMOTING INTERACTION • PROVIDE A “DOCKING SITE “ FOR INTERACTION OF OTHER PROTEINS

26. INTRACELLULAR RECEPTORS • LIPID SOLUABLE MOLECULES • MAY BE TRANSCRIPTION FACTORS ENHANCING OR SUPPRESSING GENE EXPRESSION

27. NEURAL NETWORKS ARE SPECIAL CASES OF SIGNALLING NETWORKS IN CELLULAR SYSTEMS • D.C. MIKULECKY “A COMPARISON BETWEEN THE FORMAL DESCRIPTION OF REACTION AND NEURAL NETWORKS: A NETWORK THERMODYNAMIC APPRAOACH” IN “BIOMEDICAL ENGINEERING: OPENING NEW DOORS”, D. C. MIKULECKY AND A. M. CLARKE, EDS., NYU PRESS, pp 67-74, 1990.

28. GENERALIZING NEURAL NETWORKS TO MODEL CELL SIGNALLING: D. BRAY • D. BRAY “INTRACELLULAR SIGNALLING AS A PARALLEL DISTRIBUTED PROCESS” J. theor. BIOL 143:215-231 (1990) • BRAY IN “THE MOLECULAR BIOLOGY OF THE CELL” Alberts, Bray, et al . In CHAP. 15 “CELL SIGNALLING” “THE LOGIC OF INTRACELLULAR SIGNALLING: LESSONS FROM COMPUTER-BASED ‘NEURAL NETWORKS’”

29. GENERALIZING NEURAL NETWORKS TO MODEL CELL SIGNALLING: JEFF PRIDEAUX , JOY WARE • “FROM NEURAL NETORKS TO CELL SIGNALLING: CHEMICAL COMMUNICATIONS IN CELL NETWORKS” J. BIOL. SYSTEMS 1:131-146 (1993) • “INTERCONNECTED STRUCTURES IN LIVING SYSTEMS ARE UBIQUITOUS. THUS, IN A SENSE, EVERYTHING CAN BE VIEWED AS A NETWORK.”

30. NEURAL NETWORKS ARE SPECIAL CASES OF SIGNALLING NETWORKS IN CELLULAR SYSTEMS • CHEMICAL SIGNALS THROUGHOUT THE LIVING SYSTEM • DISTRIBUTED SYSTEMS IN ALL CASES • USE IT OR LOOSE IT HEBBIAN LEARNING OFTEN OPERATIVE

31. EMERGENT PROPERTIES OF NETWORKS OF BIOLOGICAL SIGNALING PATHWAYS, BY U.S. BHALLA AND R. IYENGAR • SCIENCE 283, (15 JANUARY,1999) PP 381-387 • “WE DEVELOPED THE NETWORK MODEL IN STAGES” • “THESE NETWORKS EXHIBIT EMERGENT PROPERTIES SUCH AS INTEGRATION OF SIGNALS ACROSS MULTIPLE TIME SCALES, GENERATION OF DISTINCT OUTPUTS DEPENDING ON INPUT STRENGTH AND DURATION, AND SELF-SUSTAINING FEEDBACK LOOPS • LEARNING AND MEMORY MAY OCCUR IN BIOCHEMICAL SIGNALLING PATHWAYS

32. EMERGENT PROPERTIES OBSERVED • EXTENDED SIGNAL DURATION • ACTIVATION OF FEEDBACK LOOPS • THRESHOLD EFFECTS • MULTIPLE SIGNAL OUTPUTS