CELL SIGNALLING

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CELL SIGNALLING

• D. C. MIKULECKY
• Dept. Physiology

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WHAT IS A SIGNAL?

• SEMIOTICS
• INFORMATION THEORY
• NERVOUS SYTEM
• ENDOCRINE
• PARACRINE
• ENDOCRINE
• ANTIBODIES AND OTHER FOREIGN SUBSTANCES
• PARALLEL PROCESSING

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CHEMICAL SIGNALS

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

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ELEMENTS OF CELL SIGNALLING MECHANISMS

• SIGNAL MOLECULES
• RECEPTORS
• SIGNAL TRANSDUCTION

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SIGNAL MOLECULES (FIRST MESSENGERS)

• NEUROTRANSMITTERS
• HORMONES
• LOCAL MEDIATORS

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EXAMPLES OF SIGNALLING MOLECULES
(SEE TABLE 1 IN TEXT)
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RECEPTORS

• CELL MEMBRANE HYDROPHILIC SIGNAL MOLECULES
  (POLYPEPTIDES, CATECHOLAMINES)
• CYTOPLASMIC HYDROPHOBIC SIGNAL MOLECULES
  (STEROIDS, VITAMIN D, THYROID HORMONE)

BOUND TO CARRIER PROTEIN
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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)

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EXAMPLES OF ANTAGONISTS

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

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REGULATION OF RECEPTOR QUANTITY AS A CONTROL
MECHANISM

• DESENSITIZATION BY DOWNREGULATION DUE TO
  INCREASED ANTAGONIST LEVELS
• INTERNALIZATION OF COMPLEX BY ENDOCYTOSIS
• RECEPTOR SYNTHESIS (UPREGULATION)

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AN EXAMPLE OF RECEPTOR RECYCLING
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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 MEMBRANESEVEN ALPHA HELICES OF ABOUT 25
  HYDROPHOBIC AA
• SEE FIG 8 IN TEXT

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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

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SOME MOLECULES THAT SIGNAL THROUGH
G-PROTEIN-COUPLED RECEPTORS

• CALCIUM
• ADENOSINE
• EPINEPHRINE
• ANGIOTENSIN
• ACETYLCHOLINE
• VASOPRESSIN

• INTERLEUKIN-8
• TSH
• GLUTAMINE
• PROSTAGLANDIN E2
• SOMATOSTATIN
• CCK

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

• ADENYL CYCLASE
• LIGAND GATED CHANNELS
• INOSITAL TRIPHOSPHATE AND DIAGLYCEROL

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G PROTEINS

• INTEGRAL MEMBRANE PROTEIN
• COUPLED TO ADENYLATE CYCLASE
• Gs STIMULATES
• Gi INHIBITS

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ADENYL CYCLASE
A P P P
A
ADENYLATE CYCLASE

P - P
P
CYCLIC AMP
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CYCLIC AMP ACTIVATES PROTEIN KINASES WHICH
PHOSPHORYLATE PROTEINS

• STRUCTURAL EFFECTS
• CALCIUM FLUXES
• GENE EXPRESSION
• METABOLIC EFFECTS
• MEMBRANE EFFECTS

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SOME HORMONES THAT USE C-AMP AS SECOND MESSENGER

• ACTH
• EPINEPHRINE
• GLUCAGON
• LH
• PTH
• TSH
• FSH

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LIGAND GATED CALCIUM CHANNELS

• CONFORMATIONAL CHANGE IN RECEPTOR CAN OPEN
  CHANNEL
• CAN TRIGGER ACTION POTENTIAL OR
• PROMOTE CALCIUM TRIGGERED INTRACELLULAR RESPONSE

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INOSITOL TRIPHOSPHATE AND DIACYLGLYCEROL

• BREAKDOWN OF MEMBRANE PHOSPHOLIPID
  PHOSPHITYDYLINOSITOL BIPHOSPHATE
• SPECIFIC PHOSPHOLIPASE C

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REMOVAL OF SECOND MESSENGERS FROM THE CYTOSOL

• CYCLIC AMP PHOSPHODIESTERASE
• CALCIUM PUMPED OUT OF CELL OR INTO SARCOPLASMIC
  RETICULUM
• CALCIUM BINDING PROTEINS

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PROTEIN KINASES CONFORMATIONAL CHANGES

• SERIES OF PHOSPHORYLATION REACTIONS
• EACH KINASE IS SUBSTRATE FOR ANOTHER KINASE
• AMPLIFIES SIGNAL 1,000 FOLD

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PROTEIN KINASES CONFORMATIONAL CHANGES

• UNMASK ACTIVE SITE
• UNMASK BINDING SITE PROMOTING INTERACTION
• PROVIDE A DOCKING SITE FOR INTERACTION OF
  OTHER PROTEINS

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INTRACELLULAR RECEPTORS

• LIPID SOLUABLE MOLECULES
• MAY BE TRANSCRIPTION FACTORS ENHANCING OR
  SUPPRESSING GENE EXPRESSION

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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.

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GENERALIZING NEURAL NETWORKS TO MODEL CELL
SIGNALLING D. BRAY

• D. BRAY INTRACELLULAR SIGNALLING AS A PARALLEL
  DISTRIBUTED PROCESS J. theor. BIOL 143215-231
  (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

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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 1131-146 (1993)
• INTERCONNECTED STRUCTURES IN LIVING SYSTEMS ARE
  UBIQUITOUS. THUS, IN A SENSE, EVERYTHING CAN BE
  VIEWED AS A NETWORK.

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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

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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

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EMERGENT PROPERTIES OBSERVED

• EXTENDED SIGNAL DURATION
• ACTIVATION OF FEEDBACK LOOPS
• THRESHOLD EFFECTS
• MULTIPLE SIGNAL OUTPUTS