CELL SIGNALLING
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Transcript CELL SIGNALLING
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