Signal transduction

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• Cellular Signal Transduction
• M.Prasad Naidu
• MSc Medical Biochemistry,
• Ph.D.Research Scholar

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When environment changes

• Monadresponds directly.
• Multicellular organismssignal through
  elaborate system of intercellular or
  intracellular communication,and consequently
  regulate functions of organisms.

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Signaling molecule
Receptor of target cell
Signal transduction
Intracellular molecule
biological effect
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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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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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(5) Autocrine signal

• Act back to their own cells.
• Such as GF, cytokine, interferon, interleukin.

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GAS MOLECULE
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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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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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1. membrane receptors

• (1) Ligand-gate ion channels type
• (cyclic receptor)
• ligand?receptor?ion channel open or close

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(2) G Protein-Coupled Receptors
(serpentine R)

• 1) 7-helices transmembrane receptor

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2) G protein (Guanylate binding protein)

• 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.

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G protein Coupled Receptors The human genome
encodes more than 1000 Gprotein Coupled Receptors
(GPCR), that transduce messages as diverse as
light, smells, taste, and hormones An example
is the beta-adrenergic receptor, that mediates
the effects of epinephrine on many tissues
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3) Classes of G protein

• Gs? ?s?AC?cAMP?
• Gi? ?i?AC?cAMP?
• Gq? ?q ?PI-PLC?IP3DAG
• Go? ?o?ion channel
• Gt? ?t ?cGMP PDE?cGMP?
• Rhodopsin

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Gs vs Gi vs Gq Gs and Gi coupled to adenylate
cyclase ? ? cAMP
G q coupled to phospholipase C ? ? Ca2
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Gs vs. Gi Regulation of Adenylate Cyclase
Activity
Gs stimulates adenylate cyclase
Gi inhibits adenylate cyclase
e.g. epinephrine can increase or decrease
intracellular cAMP concentrations, depending upon
the receptor to which it binds
? adrenergic receptors couple to Gs, whereas ?2
adrenergic receptors couple to Gi
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• Glucagon
• ?-adrenaline ??s ?AC?
• ACTH
• ?-adrenaline
• angiotensin ?
• acetylcholine(M2 M4)
• GF release inhibitory factor

??i?AC?
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Inhibition of Gs and Gi by Bacterial Toxins
Cholera toxin effects on Gs ADP ribosylation of
an Arg residue in the ?s subunit of Gs?
inhibition of associated GTPase activity
Pertussis toxin effects on Gi ADP ribosylation
of a Cys residue in the ?i subunit of Gi ? an
inability to inhibit adenylate cyclase activity.
Thus, both toxins cause increased intracellular
cAMP concentrations!
2000 by W. H. Freeman and Company. All rights
reserved.
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(3) Single transmembrane a-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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Insulin
Intracellular insulin effects
Cytosol
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(4) Guanylate cyclase (GC) receptor
Membrane receptor ANP Soluble receptor NO, CO
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2. Intracellular receptor (transcription
regulated receptor)

• Intracellular R is trans-acting element
  cis-acting element gene expression
• Localized in the cytosol and/or in the nucleus.
• ligand Steroid H, Vit D3, Thyroxine

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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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5. Function of receptor

• (1) Recognize the special ligand
• (2) Binding to special ligand
• (3) Signal transduction biological effect

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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-?B pathway

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1. cAMP dependent-protein kinase A pathway

H
R
G protein
cAMP
AC
PKA
Phosphorylation of Es or functional proteins
Biological effects
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(1) cAMP metabolism

PDE
AC
PDE Phosphodiesterase
AC Adenylate cyclase
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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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2. Ca2 dependent PK pathway

• (1) Ca2 -DAG -dependent PKC pathway

PIP2
G protein
PLC
R
H
IP3
DG
Ca2
ER
PKC
Phosphorylation of Es or functional proteins
Biological effects
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1) Function of DG and IP3

• IP3 R?open of Ca2 channel ?Ca2? from
  ER
• Ca 2i 0.01-1 ?mol/L(10-7 mol/L )
• Ca 2o 2.5mmol/L(10-3 mol/L )
  
• 500010000

DG
PKC ?
Ca2
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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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(2) Ca2-CaM dependent protein kinase pathway
H
R
G protein
PLC

IP3
Ca2
CaM
CaMK
Phosphorylation of Es or functional proteins
Biological effects
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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

ANP
NO, CO
Receptor- linked GC
Soluble GC
cGMP
PKG
Phosphorylation of Es or functional proteins
Biological effects
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(1) cGMP
GC
PDE

• (2) Function of PKG
• Ser/Thr- P of protein and E

GC Guanylate cyclase
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• ANP(atrial natriuretic peptides)
• ?
• GC NO
• ?
• cGMP
• ?
• PKG
• ?
• Vascular dilatation

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4. Tyrosine-protein kinase pathway (TPK)

• TPK receptor is related to proliferation,
  differentiation, dissociation, carcinomatous
  change.
• TPK
• receptor TPKMembrane.
• non receptor TPKcytosol

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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
• MAPKs belong to a family of serine/threonine
  kinases (kinases add
• phosphate groups to/phosphorylate other proteins)
• They participate in cell growth,
  differentiation, transformation,
• apoptosis (controlled cell death) and others

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EGF, PDGF
GRB2-P
receptor TPK
Ras-GTP
SOS-P
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• (2) JAKs-STAT pathway
• JAKs(JANUS KINASES)
• STAT Signal transductors and activator of
  transcription

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interferons GH
Plasma membrane
STAT complex
inactive STAT
Nuclear membrane
transcription
gene
Interferons response element
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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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Proteins and peptides
Hormones, cytokines
Effect by membrane receptors
Amino acid derivatives
Catecholamines
Fatty acid derivatives
Extracellular molecules
Prostaglandins
Effect by intracellular receptors
Signal molecules
Steroid hormones, Thyroxine, VD3
Intracellular molecules
cAMP, cGMP, IP3, DG, Ca2
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THANK YOU