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CELL SIGNALLING
D. C. MIKULECKY
Dept. 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 SECRETED
TRAVELS FRON ONE SITE TO ANOTHER
RECEPTOR 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 AND
DERIVATIVES
HISTAMINE
GLYCINE
EPINEPHRINE
FATTY ACID
DERIVATIVES
PROSTAGLANDINS
---
TESTOSTERONE
OTHER SMALL
MOLECULES
---
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 RECEPTORS
G-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  SUBUNITS
METABOLIC SWITCHES
GTPASE ACTIVITY
BINDING 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
CALCIUM
ADENOSINE
EPINEPHRINE
ANGIOTENSIN
ACETYLCHOLINE
VASOPRESSIN
INTERLEUKIN-8
TSH
GLUTAMINE
PROSTAGLANDIN E2
SOMATOSTATIN
CCK
SIGNAL TRANSDUCTION AT THE CELL
MEMBRANE (SECOND MESSENGERS)
MEMBRANE
RECEPTOR
LIGAND
INTRACELLULAR
SIGNALS
(SECOND
MESSENGERS)
EFFECT INSIDE
CELL (VERY
OFTEN THE
NUCLEUS)
SIGNAL TRANSDUCTION AT THE CELL
MEMBRANE (SECOND MESSENGERS)
ADENYL CYCLASE
LIGAND GATED CHANNELS
INOSITAL TRIPHOSPHATE AND
DIAGLYCEROL
G PROTEINS
INTEGRAL MEMBRANE PROTEIN
COUPLED TO ADENYLATE CYCLASE
Gs STIMULATES
Gi INHIBITS
ADENYL CYCLASE
A
|
P
|
P
|
P
ADENYLATE
CYCLASE
A
+
P
CYCLIC AMP
P-P
CYCLIC AMP ACTIVATES PROTEIN KINASES
WHICH PHOSPHORYLATE PROTEINS
 STRUCTURAL EFFECTS
 CALCIUM FLUXES
 GENE EXPRESSION
 METABOLIC EFFECTS
 MEMBRANE EFFECTS
SOME HORMONES THAT USE CAMP AS SECOND MESSENGER
ACTH
EPINEPHRINE
GLUCAGON
LH
PTH
TSH
FSH
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 SITE
UNMASK BINDING SITE PROMOTING
INTERACTION
PROVIDE A “DOCKING SITE “ FOR
INTERACTION OF OTHER PROTEINS
INTRACELLULAR
RECEPTORS
LIPID SOLUABLE MOLECULES
MAY 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 COMPUTERBASED ‘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 CASES
USE 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