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