1. Signal Transduction
Dr. Nasim

2. Ligands & Receptors Ligand Receptor proteins Binding site Affinity
Neurotransmitters & drugs
Receptor proteins
ligand binds to multiple receptors
Binding site
specific point of ligand & receptor
Affinity
attraction
physical & electrical fit~

3. Receptor Activation Lock & Key Model Structure-activity relationship
Physical & electrical fit
Affinity
Activation  excitation or inhibition
Drugs
Change structure  change affinity
Agonists  activate
Antagonists  no activation ~

4. Chemical Signaling Mechanisms
Synaptic
Paracrine
Medium range intercellular signaling
Endocrine
Hormones via blood
Pheromones
Via air ~

5. Signaling Pathways Cell impermeant Cell permeant
Requires receptors in membranes
Cell permeant
Lipid soluble
Steroid hormones
Cell-associated signaling molecules
e.g., CAMs ~

6. Receptor Types Channel-linked receptors Enzyme-linked receptors
Ionotropic
Enzyme-linked receptors
Protein kinases mostly
Neurotrophin-R
G-protein-coupled receptors
Metabotropic
Intracellular receptors
Activation by cell-permeant signals ~

7. Metabotropic receptors
G protein-coupled receptors
requires GTP
Receptor indirectly controls channel
G protein-gated ion channels
2d messenger systems
neuromodulation
slower action
changes in sensitivity of neuron ~

8. G protein-gated Ion Channels
NT binds to receptor protein
activates G protein
G protein binds to channel
opens or closes
relatively fast
compared to 2d messenger systems ~

9. G protein: direct control
GDP

10. G protein: direct control
GTP *
GDP

11. G protein: direct control
GTP
Pore

12. 2d Messenger Systems NT = 1st messenger Membrane-associated components
Receptor
Transducer
Primary effector
Intracellular
2d messenger
Secondary effector ~

13. 2d Messenger Systems Slower & enduring changes Signal amplification
Multiple effectors
Signal amplification
1 NE  1000s cAMP
1000s cAMP  10,000s phosphates
Effects
Control channel
Alter properties of receptors
regulation of gene expression ~

14. 2d Messengers Calcium (Ca2+) Cyclic nucleotides Target: calmodulin
Calmodulin  protein kinases & phosphatases
Cyclic nucleotides
cAMP & cGMP
Target: protein kinases ~

15. 2d Messengers: Membrane Lipids
Precursor: PIP2
Phosphatidylinositol biphosphate
Cleaved by phospholipase C
Diacylglycerol
DAG  Protein Kinase C (membrane)
Inositol triphosphate
IP3  Ca2+ (endoplasmic reticulum) ~

16. 2d Messenger Targets Enzymes Protein Kinases Protein Phosphatases
Modulate phosphorylation
Protein Kinases
activated by: Ca2+ , cAMP, DAG, etc.
Increase phosphorylation
Protein Phosphatases
Decrease phosphorylation
activated by Ca2+/calmodulin ~

17. Nuclear Signaling Modulates protein synthesis
Slow: min
Transcriptional activator proteins
DNA  RNA  Proteins ~

18. b-adrenergic 2d Messenger System
external signal: nt
external signal: nt
norepinephrine
b adrenergic -R
Receptor
trans-
ducer
primary
effector
Receptor
trans-
ducer
primary
effector GS
adenylyl
cyclase
2d messenger
2d messenger
cAMP
secondary effector
secondary effector
protein kinase

19. b-adrenergic 2d Messenger System
NT: Norepinephrine
Membrane-associated components
Receptor: b-adrenergic
Transducer: Gs protein
Primary effector: Adenyly cyclase
Intracellular components
2d messenger: cAMP
Secondary effector: Protein kinase ~

20. G protein: Protein PhosphorylationC G
GDP PK

21. G protein: Protein PhosphorylationC G
GTP
ATP
cAMP PK

22. G protein: Protein PhosphorylationC G
GTP
ATP
cAMP P PK

23. G protein: Protein PhosphorylationC G
GTP
Pore
ATP P
cAMP PK