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CELL SIGNALLING
D. C. MIKULECKYDept. Physiology
WHAT IS A SIGNAL?
SEMIOTICS INFORMATION THEORY NERVOUS SYTEM ENDOCRINE PARACRINE ENDOCRINE ANTIBODIES AND OTHER FOREIGN SUBSTANCES PARALLEL PROCESSING
CHEMICAL SIGNALS
SIGNALING MOLECULE IS SECRETEDTRAVELS FRON ONE SITE TO
ANOTHERRECEPTOR AT TARGET BINDING TO RECEPTOR EFFECTS
SOME CHANGE
ELEMENTS OF CELL SIGNALLING MECHANISMS
SIGNAL MOLECULES
RECEPTORS
SIGNAL TRANSDUCTION
SIGNAL MOLECULES (FIRST MESSENGERS)
NEUROTRANSMITTERS
HORMONES
LOCAL MEDIATORS
EXAMPLES OF SIGNALLING MOLECULES
TYPE OF MOLECULE LOCAL MEDIATOR NEUROTRANSMITTER HORMONE
PEPTIDES --- NEUROPEPTIDES VASOPRESSIN
POLYPEPTIDES --- --- INSULIN
AMINO ACIDS ANDDERIVATIVES
HISTAMINE GLYCINE EPINEPHRINE
FATTY ACIDDERIVATIVES
PROSTAGLANDINS --- TESTOSTERONE
OTHER SMALLMOLECULES
--- ACETYLCHOLINE ---
(SEE TABLE 1 IN TEXT)
RECEPTORS
CELL MEMBRANE: HYDROPHILIC SIGNAL MOLECULES (POLYPEPTIDES, CATECHOLAMINES)
CYTOPLASMIC: HYDROPHOBIC SIGNAL MOLECULES (STEROIDS, VITAMIN D, THYROID HORMONE*)
*BOUND TO CARRIER PROTEIN
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”)
EXAMPLES OF ANTAGONISTS
PROPRANOLOL BLOCKS THE EFFECTS OF CATECHOLAMINES BY BINDING TO THEIR RECEPTORS
SPIRONOLACTONE BLOCKS ALDOSTERONE (DIURETIC)
REGULATION OF RECEPTOR QUANTITY AS A CONTROL MECHANISM
DESENSITIZATION BY DOWNREGULATION DUE TO INCREASED ANTAGONIST LEVELS
INTERNALIZATION OF COMPLEX BY ENDOCYTOSIS
RECEPTOR SYNTHESIS (UPREGULATION)
AN EXAMPLE OF RECEPTOR RECYCLING
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
G-PROTEINS ARE ASSOCIATED WITH THE RECEPTORS
HETEROTRIMERS: , , AND SUBUNITSMETABOLIC SWITCHESGTPASE ACTIVITYBINDING OF LIGAND CAUSES
CONFORMATIONAL CHANGE IN SUBUNIT EXCHANGING GDP FOR GTP
FREE COMPLEX INTERACTS WITH INTRACELLULAR PROTEINS
SOME MOLECULES THAT SIGNAL THROUGH G-PROTEIN-COUPLED
RECEPTORS
CALCIUMADENOSINEEPINEPHRINEANGIOTENSINACETYLCHOLINEVASOPRESSIN
INTERLEUKIN-8TSHGLUTAMINEPROSTAGLANDIN
E2SOMATOSTATINCCK
SIGNAL TRANSDUCTION AT THE CELL MEMBRANE (SECOND MESSENGERS)
LIGAND
MEMBRANE
RECEPTOR
INTRACELLULAR SIGNALS (SECOND MESSENGERS)
EFFECT INSIDECELL (VERY OFTEN THE NUCLEUS)
SIGNAL TRANSDUCTION AT THE CELL MEMBRANE (SECOND MESSENGERS)
ADENYL CYCLASELIGAND GATED CHANNELSINOSITAL TRIPHOSPHATE AND
DIAGLYCEROL
G PROTEINS
INTEGRAL MEMBRANE PROTEINCOUPLED TO ADENYLATE CYCLASEGs STIMULATES Gi INHIBITS
ADENYL CYCLASE
A|P|P|P
ADENYLATE CYCLASE
A
P
+ P - P
CYCLIC AMP
CYCLIC AMP ACTIVATES PROTEIN KINASES WHICH PHOSPHORYLATE PROTEINS
STRUCTURAL EFFECTS CALCIUM FLUXES GENE EXPRESSION METABOLIC EFFECTS MEMBRANE EFFECTS
SOME HORMONES THAT USE C-AMP AS SECOND MESSENGER
ACTHEPINEPHRINEGLUCAGONLHPTHTSHFSH
LIGAND GATED CALCIUM CHANNELS
CONFORMATIONAL CHANGE IN RECEPTOR CAN OPEN CHANNEL
CAN TRIGGER ACTION POTENTIAL OR
PROMOTE CALCIUM TRIGGERED INTRACELLULAR RESPONSE
INOSITOL TRIPHOSPHATE AND DIACYLGLYCEROL
BREAKDOWN OF MEMBRANE PHOSPHOLIPID: PHOSPHITYDYLINOSITOL BIPHOSPHATE
SPECIFIC PHOSPHOLIPASE C
REMOVAL OF SECOND MESSENGERS FROM THE CYTOSOL
CYCLIC AMP PHOSPHODIESTERASE
CALCIUM PUMPED OUT OF CELL OR INTO SARCOPLASMIC RETICULUM
CALCIUM BINDING PROTEINS
PROTEIN KINASES: CONFORMATIONAL CHANGES
SERIES OF PHOSPHORYLATION REACTIONS
EACH KINASE IS SUBSTRATE FOR ANOTHER KINASE
AMPLIFIES SIGNAL 1,000 FOLD
PROTEIN KINASES: CONFORMATIONAL CHANGES
UNMASK ACTIVE SITEUNMASK BINDING SITE
PROMOTING INTERACTIONPROVIDE A “DOCKING SITE “
FOR INTERACTION OF OTHER PROTEINS
INTRACELLULAR RECEPTORS
LIPID SOLUABLE MOLECULESMAY BE TRANSCRIPTION FACTORS
ENHANCING OR SUPPRESSING GENE EXPRESSION
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.
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’”
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.”
NEURAL NETWORKS ARE SPECIAL CASES OF SIGNALLING NETWORKS IN CELLULAR SYSTEMS
CHEMICAL SIGNALS THROUGHOUT THE LIVING SYSTEM
DISTRIBUTED SYSTEMS IN ALL CASESUSE IT OR LOOSE IT HEBBIAN
LEARNING OFTEN OPERATIVE
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
EMERGENT PROPERTIES OBSERVED
EXTENDED SIGNAL DURATION
ACTIVATION OF FEEDBACK LOOPS
THRESHOLD EFFECTS
MULTIPLE SIGNAL OUTPUTS