third messanger
TRANSCRIPT
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Chapter 15
Cellular Signal Transduction
The biochemistry and molecular biology department of CMU
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When environment changes:
Monad——responds directly.
Multicellular organisms——signal through elaborate system of intercellular or intracellular communication , and consequently regulate functions of organisms.
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Signaling molecule
Receptor of target cell
Intracellular molecule
biological effect
Signaltransduction
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§1 Signaling Molecules
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Signaling molecules
• Signaling molecules, which are released by signal-producing cells, reach and transfer biological signals to their target cells to initiate specific cellular responses.
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• Extracellular molecules
• Intracellular molecules
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1. Extracellular molecules
protein & peptides: Hormone, cytokine
AA & its derivatives: Gly, Glu, adrenaline, thyroxine
Steroid: Sex Hormone,
glucocorticosteroid
Fatty acid derivatives: prostaglandin
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(1) Paracrine signaling (local chemical mediators)
• Secreted by common cells.
• Reach neighboring target cells by passive diffusion.
• Time of action is short.
• Such as GF, PG
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(2) Endocrine signal
• Secreted by endocrine cells.
• Reach target cells by blood circulation.
• Time of action is long.
• Such as insulin, thyroxine, adrenalin
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(3) Synaptic signal (neurotransmitters)
• Secreted by neuronal cells.
• Reach another neuron by synaptic gap.
• Time of action is short.
• Such as Acetylcholine (Ach), noradrenaline
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(4) Gaseous signal
• Simple structure, half life is short and active in chemistry .
• Such as NO, CO.
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GAS MOLECULE
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(5) Autocrine signal
• Act back to their own cells.
• Such as GF, cytokine, interferon, interleukin.
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2. Intracellular molecule
• Ca2+ ions
• DG, ceramide lipid derivatives
• IP3 carbohydrate
derivatives
• cAMP cGMP nucleotides
• Ras, JAK, Raf proteins
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Second messenger:
Small molecules synthesized in cells in response to an external signal are the second messengers, which are responsible for intracellular signal transduction.
Such as Ca2+, DG, Cer, IP3, cAMP, cGMP
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Third messengers:
Third messengers are the molecules which transmit message from outside to inside of nucleous or from inside to outside of nucleous, also called DNA binding protein.
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Effect by membrane receptors
Effect by intracellular receptors
Intracellular molecules
Extracellular molecules
Signal molecules
cAMP, cGMP, IP3, DG, Ca2+
Proteins and peptides:
Hormones, cytokines
Amino acid derivatives:
Catecholamines
Fatty acid derivatives:
Prostaglandins
Steroid hormones, Thyroxine, VD3
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§2 Receptor
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Receptor
Receptors are specific membrane proteins, which are able to recognize and bind to corresponding ligand molecules, become activated, and transduce signal to next signaling molecules.
Glycoprotein or Lipoprotein
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ligand A small molecule that binds
specifically to a larger one; for example, a hormone is the ligand for
its specific protein receptor.
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• Membrane receptors
membrane
Glycoprotein
• Intracellular receptors
Cytosol or nuclei
DNA binding protein
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(1) Ligand-gate ion channels type
(cyclic receptor)
ligand→receptor→ion channel open or close
1. membrane receptors
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1) 7-helices transmembrane receptor
(2) G Protein-Coupled Receptors (serpentine R)
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Cytosolicside
Oligosaccharideunit
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• G protein refers to any protein which binds to GDP or GTP and act as signal transduction.
• G proteins consist of three different subunits (, , -subunit). • -subunit carries GTPase activity, binding and hydrolysis of GTP.
2) G protein (Guanylate binding protein)
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Gs→ s→AC→cAMP↑
Gi→ i→AC→cAMP↓
Gq→ q →PI-PLC→IP3+DAG
Go→ o→ion channel
Gt→ t →cGMP PDE→cGMP→
Rhodopsin
3) Classes of G protein
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Glucagon
-adrenaline →s →AC↑
ACTH
-adrenaline
angiotensin Ⅱ
acetylcholine(M2 M4)
GF release inhibitory factor
→i→AC↓
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Ribosylation of Arg of G
G s -ATP Gs -ADP
AC
cAMP Cl- + H2O Cavity of intestinediarrheaHCO3
-
Cholera toxin
ATPase
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Pertussis toxin
i -ADP-ribosylation
Gi
AC↑
allergy of histamine
cAMP ↑
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AC
cGMP PDE (phosphodiesterase )
PLC
PLA2
Channel protein
4) Effect proteins of G protein
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cAMP
ATP
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5) Pathway of G protein linked receptor
H R G protein Es
secondary messeger
Protein kinase
Phophorylation of Es or functional protein
Biological effect
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(3) Single transmembrane α-helix receptor
• Tyrosine protein kinase Receptor
(catalytic receptor)
IGF - R, EGF - R
• Non tyrosine protein kinase Receptor
Growth Hormone R, interferon R
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Tyrosine protein kinase Receptoror receptor tyrosine kinase (RTK)
Cys-richdomain
Immunoglobulin-like
domain
EGFR IGF-1R PDGFR FGFR
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Intracellularinsulin effectsCytosol
Insulin
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Non-receptor tyrosine kinase (NRTK)
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Domain of Downstream molecules of TPKR
SH2 domain (Scr homology 2 domain)
SH3 domain
PH domain (pleckstrin homology domain)
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Membrane receptor –ANP
Soluble receptor – NO, CO
(4) Guanylate cyclase (GC) receptor
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2. Intracellular receptor (transcription regulated
receptor) Intracellular R is trans-acting
elememt cis-acting element gene expression
Localized in the cytosol and/or in the nucleus.
ligand: Steroid H, VD3, Thyroxine
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3. Properties of binding of H and R
• highly specificity
• highly affinity
• saturation
• reversible binding
• special function model
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4. Control of receptor activity
• Phosphorylation or dephosphorylation of R
• Phospholipid of membrane
• Enzyme catalyzed hydrolysis
• G protein regulation
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(1) Recognize the special ligand
(2) Binding to special ligand
(3) Signal transduction biological effect
5. Function of receptor
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§3 Pathway of Signal
Transduction
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Signal transduction mediated by membrane receptor
• cAMP dependent-protein kinase A pathway
• cGMP dependent PKG pathway • Ca2+ dependent PK pathway • Tyrosine protein Kinase pathway
• NF-κB pathway • TGF- βpathway
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1. cAMP dependent-protein kinase A pathway
H R
G protein
Phosphorylation of Es or functional proteins
Biological effects
PKA
cAMPAC
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(1) cAMP metabolism
ATPMg2+
PPi
cAMP
H2OMg2+ 5'-AMP
AC PDE
AC : Adenylate cyclase
PDE : Phosphodiesterase
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PDE
H2O
N
N N
N
NH2
O
H
OHOH
CH2
H
H H
OPO
O
O
PO
O
O
P
O
O
O ATP
ACPPi
N
N N
N
NH2
O
H
OHO
CH2
H
H H
O
PO
O
cAMP
N
N N
N
NH2
O
H
OHOH
CH2
H
H H
OPO
O
O
5'-AMP
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(2) Mechanism of cAMP effect
Activate cAMP-dependent protein kinase (PKA).
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(3) PKA effect
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Phosphorylate specifically
Ser/Thr residues in several proteins
( 1 ) Regulation of metabolism
( 2 ) Regulation of gene
expression
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hormons: glucagon, epinephrine
inactive AC active AC
ATP cAMP
inactive PKA active PKA
phosphorylase b kinase
phosphorylase b kinase
P
ATP
ADP
H2O
Pi
phosphorylase b
P
P
ATP ADP
Pi
H2OATP ADP
glycogen synthase
glycogen synthase
P
H2OPi protein phosphatase-1
(active) (inactive)
inhibitor-1 (active)
inhibitor-1 (inactive)
phosphorylase a
ATP
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CRE : cAMP response element
(TGACGTCA)
CREB: CRE binding protein
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DNACRE
CREB
PKA
P
Transcription
mRNA
CREB
PKA
P
CREBP
CR
EBP
CR
EB
P
CREBP
CR
EB
P
CR
EB
P
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2. Ca2+ dependent PK pathway
(1) Ca2+ -DAG -dependent PKC pathway
H R
PIP2
G protein PLC
IP3 DG
ERPKC
Ca2+ PS
Biological effects
Phosphorylation of Es or functional proteins
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[Ca 2+]i 0.01-1 mol/L ( 10-7 mol/L )
[Ca 2+]o 2.5mmol/L ( 10-3 mol/L )
5000~10000×
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1 ) Function of DG and IP3
IP3 + R→open of Ca2 + channel →[Ca2 + ]↑
PS, Ca2 +DG PKC ↑
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2 ) Function of PKC
• regulation of metabolism
PKC →Ser/Thr-P of R, enzyme,
Protein of Mb.
• Gene expression
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Late response:
Trans-acting factor-P
Third messengerImmediate early genes
Third messenger-P
Activate genes
Cell proliferation
PKC
PKC
Early response:
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(2) Ca2 + -CaM dependent protein kinase pathway
H R G protein PLC
IP3
Ca2+ CaM
CaMK
Biological effects
Phosphorylation of Es or functional proteins
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Calmodulin (CaM ): Ca2 + binding protein
4 Ca2 + + CaM → Ca2 + - CaM
↓ CaM kinase↑
↓ Ser/Thr - P ↓
Ca2 + pump, AC ↑ GC ↑
Es (glycogen synthase, phosphorylase kinase)
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3. cGMP-dependent PKG pathway
Biological effects
Phosphorylation of Es or functional proteins
ANPNO, CO
Soluble GC
PKG
cGMPReceptor-linked GC
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(1) cGMP
(2) Function of PKG
Ser/Thr- P of protein and E
Mg2+
PPi H2O
Mg2+GTP cGMP 5'-GMP
GC PDE
GC: Guanylate cyclase
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ANP ( atrial natriuretic peptides ) ↓
GC NO
↓
cGMP
↓
PKG
↓
Vascular dilatation
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cis-acting elementnucleus
expression
cell memberane
phosphorylation of enzymes or proteins effects
CaM-PK
Ca2+-CaMCa2+
IP3DGcAMP cGMP
PKA PKG PKC
ATP GTP PIP2(PC)
G AC GC G PL
peptide hormonesneurotransmitters AFP
neurotransmittershypothalamic pituitrin
Ptrans-acting factor
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4. Tyrosine-protein kinase pathway (TPK)
• TPK receptor is related to proliferation, differentiation, dissociation, carcinomatous change.
• TPK :receptor TPK : Mb.
non receptor TPK : cytosol
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(1) Receptor TPK - Ras -MAPK pathway
• GRB2, SOS, Ras, Raf
• Small G protein: Ras
• MAPK (mitogen-activated protein kinase) :
MAPK 、 MAPKK 、 MAPKKK
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ÊÜÌå ÐÍTPKϸ°ûĤ
EGF, PDGF
receptor TPK Ras - GTPSOS - PGRB2 - P
Raf - P
MAPKK - P
MAPK - Ptrans-acting factor
expression
nucleus
- P
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(2) JAKs - STAT pathway
ligand
non TPK receptor
JAKs STAT
gene expression
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• JAKs
• STAT: Signal transductors and
activator of transcription
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¸ÉÈÅËØÓ¦´ð Ôª¼þ
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»ùÒò
£ PP£
JAK
11391
84
48
113
P
91P 84 P
48
113
91 84P P
P
interferons
inactive STAT
Plasma membrane
STAT complex
Nuclear membrane
geneInterferons response element
transcription
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Dimerization of Receptor
Interferon
Autophosphorylation of JAK
Phosphorylation of STAT
Nuclear translocation of STAT
Interferon response element
Expression of gene
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5. Nuclear factor-κB pathway
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6. TGF-βpathway
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Intracellular receptor (DNA transcription regulated
receptor)
• Steroid H, VD3, Thyroxine
• Cytosolic R: glycocorticosteroid H
• Nuclear R: thyroxine, estrogen, androgen, progesterone
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Serum binding proteinWith bound bormone