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

2. Monad——responds directly.
Multicellular organisms——signal
through elaborate system of
intercellular or intracellular
communication，and consequently
regulate functions of organisms.

3. Signaling molecule
Receptor of target cell
Intracellular molecule
biological effect
Signal
transduction

4. • Signaling molecules, which are
released by signal-producing cells,
reach and transfer biological signals
to their target cells to initiate specific
cellular responses.

5. protein & peptides: Hormone, cytokine
AA & its derivatives:
Gly, Glu, adrenaline, thyro
xine
Steroid: Sex Hormone,
glucocorticosteroid
Fatty acid derivatives: prostaglandin

6. • Secreted by common cells.
• Reach neighboring target cells by
passive diffusion.
• Time of action is short.
• Such as GF, PG

7. • Secreted by endocrine cells.
• Reach target cells by blood circulation.
• Time of action is long.
• Such as insulin, thyroxine, adrenalin

8. • Secreted by neuronal cells.
• Reach another neuron by synaptic
gap.
• Time of action is short.
• Such as Acetylcholine
(Ach), noradrenaline

9. • Simple structure, half life is short
and active in chemistry .
• Such as NO, CO.

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

11. GAS MOLECULE

12. • Ca2+ ions
• DG, ceramide lipid derivatives
• IP3 carbohydrate
derivatives
• cAMP cGMP nucleotides
• Ras, JAK, Raf proteins

13. 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

14. 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.

15. 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

16. ligand
A small molecule that binds
specifically to a larger one; for
example, a hormone is the ligand for
its specific protein receptor.

17. (1) Ligand-gate ion channels type
(cyclic receptor)
ligand→receptor→ion channel open or
close

20. 1) 7-helices transmembrane
receptor

21. Cytosolic
side
Oligosaccharide
unit

22. • 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.

23. 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:…

26. Gs→ s→AC→cAMP↑
Gi→ i→AC→cAMP↓
Gq→ q →PI-PLC→IP3+DAG
Go→ o→ion channel
Gt→ t →cGMP PDE→cGMP→
Rhodopsin

30. Gs vs Gi vs Gq
Gs and Gi coupled to adenylate cyclase   [cAMP]
G q coupled to phospholipase C   [Ca2+]

31. 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

32. Glucagon
-adrenaline →s →AC↑
ACTH
-adrenaline
angiotensin Ⅱ
acetylcholine(M2 M4)
GF release inhibitory factor
→i→AC↓

33. 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.

34. • Tyrosine protein kinase Receptor
(catalytic receptor)
IGF－R, EGF－R
• Non tyrosine protein kinase Receptor
Growth Hormone R, interferon R

37. Intracellular
insulin effectsCytosol
Insulin

38. Membrane receptor –ANP
Soluble receptor – NO, CO
(4) Guanylate cyclase (GC)
receptor

39. 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

42. • Phosphorylation or
dephosphorylation of R
• Phospholipid of membrane
• Enzyme catalyzed hydrolysis
• G protein regulation

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

44. • cAMP dependent-protein kinase A
pathway
• cGMP dependent PKG pathway
• Ca2+ dependent PK pathway
•
• Tyrosine protein Kinase pathway
• NF-κB pathway

45. H R
G protein
Phosphorylation of Es or functional proteins
Biological effects
PKA
cAMPAC

46. ATP
Mg2+
PPi
cAMP
H2O
Mg2+ 5'-AMP
AC PDE
AC： Adenylate cyclase
PDE： Phosphodiesterase

47. 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

49. (3) PKA effect

50. Phosphorylate specifically
Ser/Thr residues in several
proteins
（1）Regulation of
metabolism
（2）Regulation of gene
expression

51. hormons: glucagon, epinephrine
inactive ACactive 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
H2O
ATP ADP
glycogen
synthase
glycogen
synthase
P
H2OPi
protein
phosphatase-1
(active) (inactive)
inhibitor-1
(active)
inhibitor-1
(inactive)
phosphorylase a
ATP

53. (1) Ca2+ -DAG -dependent PKC pathway
H R
PIP2
G protein PLC
IP3 DG
ER
PKC
Ca2+
Biological effects
Phosphorylation of Es or functional proteins

55. IP3 + R→open of Ca2＋
channel →[Ca2＋]↑ from ER
[Ca 2+]i 0.01-1 mol/L（10-7 mol/L ）
[Ca 2+]o 2.5mmol/L（10-3 mol/L ）
5000~10000×
Ca2＋
DG PKC ↑

57. • regulation of metabolism
PKC →Ser/Thr-P of R, enzyme,
Protein of Mb.
• Gene expression

59. H R G protein PLC
IP3
Ca2+ CaM
CaMK
Biological effects
Phosphorylation of Es or functional proteins

60. Ca2＋ binding protein
4 Ca2＋+ CaM → Ca2＋- CaM
↓
CaM kinase↑
↓
Ser/Thr - P
↓
Ca2＋ pump, AC ↑ GC ↑
Es (glycogen synthase, phosphorylase
kinase)

62. Biological effects
Phosphorylation of Es or functional proteins
ANP
NO, CO
Soluble GC
PKG
cGMP
Receptor-
linked GC

63. (2) Function of PKG
Ser/Thr- P of protein and E
Mg2+
PPi H2O
Mg2+
GTP cGMP 5'-GMP
GC PDE
GC: Guanylate cyclase

64. ANP（atrial natriuretic peptides）
↓
GC NO
↓
cGMP
↓
PKG
↓
Vascular dilatation

65. cis-actingelement
nucleus
expression
cell memberane
phosphorylationof enzymes or proteins effects
CaM-PK
Ca2+
-CaMCa2+
IP3
DGcAMP cGMP
PKA PKG PKC
ATP GTP PIP2(PC)
GAC GC GPL
peptide hormones
neurotransmitters AFP
neurotransmitters
hypothalamic pituitrin
Ptrans-actingfactor

66. • TPK receptor is related to
proliferation, differentiation,
dissociation, carcinomatous
change.
• TPK：
receptor TPK：Membrane.
non receptor TPK：cytosol

67. • 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

69. ÊÜÌåÐÍTPK
ϸ
°û
Ä
EGF, PDGF
receptor TPK Ras－GTP
SOS－P
GRB2－P
Raf－P
MAPKK－P
MAPK－P
trans-acting factor
expression
nucleus
－P

70.  (2) JAKs－STAT pathway
• JAKs(JANUS KINASES)
• STAT: Signal transductors and
activator of transcription

71. ÖÊĤ
¸ÉÈÅËØÓ¦´ðÔª¼þ
ºËĤ
»ùÒò
£- PP£-
JAK
113
91
84
48
113
P
91P 84 P
48
113
91 84P P
P
interferons & GH
inactive STAT
Plasma membrane
STAT complex
Nuclear membrane
gene
Interferons response element
transcription

73. • Steroid H, VD3, Thyroxine
• Cytosolic R: glycocorticosteroid H
• Nuclear R:
thyroxine, estrogen, androgen,
progesterone

75. 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