1. Signal transduction
The process of converting extracellular signals into cellular responses.
extracellular signaling molecules (ligands)
synthesized and released by signaling cells
produce a specific response only in target cells that have receptors for the signaling molecules
Receptor
protein that specifically binds a signaling molecule to initiate a response in a target cell
Cell responses : changes in gene expression, morphology, movements…

2. Signal transduction

3. kinase cascade
a series of protein kinases that phosphorylate each other in succession
amplifies the signal because a few signal molecules can elicit a large cell response

4. Hormones are often present at mico or nanogram/liter quantities in the blood. Amplification creates massive effects in the target cell

5. Signal transduction
Communication by extracellular signals usually involves six steps:
(1) synthesis and
(2) release of the signaling molecule by the signaling cell
(3) transport of the signal to the target cell
(4) detection of the signal by a specific receptor protein
(5) change in cellular metabolism, function, or development triggered by the receptor-signal complex
(6) removal of the signal, which often terminates the cellular response

6. Classification of hormones based on solubility and receptor location
Small lipophilic molecules
diffuse across the plasma membrane and interact with intracellular receptors
steroids, thyroxine and retinoic acid
Water-soluble hormones with cell-surface receptors
Peptide hormones (insulin, growth factors, glucagon)
Small charged molecules
epinephrine, histamine
Lipophilic hormones with cell surface receptors
Prostaglandins (prostacyclins, thromboxanes, leukotrienes )

7. Two general types of receptors
Cell surface receptors
LIGAND – hydrophilic signaling molecules
Intracellular receptors
LIGAND – hydrophobic signaling molecules

8. Major classes of cell surface receptors
G-protein coupled receptors
epinephrine, serotonin, glucagon receptors
Ion channel receptors
Acetylcholine receptor
Tyrosine kinase-linked receptors
receptors for cytokines, growth factors
Receptors with intrinsic enzymatic activity
receptors for insulin and growth factors

9. TYPES OF SECOND MESSENGERS
GASES NO
H2S  CO
HYDROPHOBIC
Diacylglycerol
Phosphatidylinositols
HYDROPHILIC
cAMP
cGMP
IP3
Ca2+.
3’,5’ cyclic AMP (cAMP)
3’,5’ cyclic GMP (cGMP)
1,2 diacylglycerol (DAG)
inositol 1,4,5 triphosphate (IP3)
inositol phospholipids (phosphoinositides)
Ca++

10. Signaling via G-protein-coupled receptors (GPCR)
G-Proteins – GTP-binding proteins
Trimeric proteins ( α β γ )
Coupled directly to activated receptors
GTPases – convert GTP to GDP + Pi
ACTIVE- when GTP is bound
INACTIVE – when GDP is bound

11. G-protein coupled receptor

12. G-protein coupled receptor

13. Cyclic AMP (cAMP)
Second messenger produced from hydrolysis of pyrophosphate from ATP
Synthesized by Adenylyl Cyclase
Degraded by cAMP phosphodiesterase to form 5’AMP.

14. Cyclic-AMP-dependent Protein Kinase (PKA) Mediates Most of the Effects of Cyclic AMP

15. cAMP activate glycolysis

16. How gene transcription is activated by a rise in cyclic AMP concentration

17. G Proteins Activate Inositol Phospholipid Signaling Pathway
Many G-Protein-Linked receptors exert their effects mainly via G proteins that activate the plasma-membrane-bound enzyme phospholipase C
Phosphatidyl inositol 4,5-bisphosphate  diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3)
the signaling pathway splits into two branches.
IP3 releases Ca++ from ER
DAG together with bound Ca++ activates protein kinase C
C-Kinase phosphorylates cell proteins

18. Diacylglycerol
Diacylglycerol stimulates protein kinase C activity by greatly increasing the affinity of the enzyme for calcium ions.
Protein kinase C phosphorylates specific serine and threonine residues in target proteins.
Known target proteins include calmodulin, the glucose transporter, HMG-CoA reductase, cytochrome P450 etc.

20. Receptor Kinases Receptor tyrosine kinases -membrane receptor
-when bound by a ligand, the receptor is activated by dimerization and autophosphorylation
-activated receptor adds a phosphate to tyrosine on a response protein
-an example is the insulin receptor

21. Families of receptor tyrosine kinases

24. mitogen-activated protein kinases

25. Other second messengers
cGMP is synthesized from GTP using the enzyme guanylyl cyclase
Some of the effects of cGMP are mediated through Protein Kinase G (PKG)
nitric oxide (NO) stimulates the synthesis of cGMP
cGMP serves as the second messenger for NO
Ca++: altering intracellular [Ca++ ]
Ca++ binds to, and activates an enzyme
binds to an intermediary cytosolic calcium binding protein such as calmodulin, then calmodulin bind to effector

26. Ras/Raf/MAP Pathway:
The Ras/Raf/MAP pathway mediates the effect of many growth factors and mitogens.
Ras, which is a proto-oncogene product, functions like a G-Protein and conveys the signal (by GDP/GTP exchange) from the SH2-domain protein Grb, which is phosphorylated by the receptor tyrosine kinase.
Activation of Ras, in turn, activates Raf, which is the first of a sequence of serine/threonine kinases, each of which phosphorylates, and activates, the next in line.
The last of these, MAP (Mitogen-Activated Protein) kinase, phosphorylates one or more transcription factors that initiate gene expression, resulting in a variety of cellular responses, including cell division.

28. Jak/Stat pathway
The Jak/Stat pathway is involved in responses to many cytokines.
Dimerisation of these receptors occurs when the cytokine binds, and this attracts a cytosolic tyrosine kinase unit (Jak) to associate with, and phosphorylate, the receptor dimer.
Among the targets for phosphorylation by Jak are a family of transcription factors (Stats).
These are SH2-domain proteins that bind to the phosphotyrosine groups on the receptor-Jak complex, & are themselves phosphorylated.
Thus activated, Stat migrates to the nucleus and activates gene expression.

30. Intracellular receptors

31. Ex Biochem c5-oxid phosphoryl