Download BN14 signal transduction

Signal
Transduction
Lecture 14
Ligands & Receptors
Ligand
 Neurotransmitters & drugs
 Receptor proteins
 ligand binds to multiple receptors
 Binding site
 specific point of ligand & receptor
 Affinity
 attraction
 physical & electrical fit~

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 ~

Chemical Signaling Mechanisms
Synaptic
 Paracrine
 Medium range intercellular
signaling
 Endocrine
 Hormones via blood
 Pheromones
 Via air ~

Signaling Pathways
Cell impermeant
 Requires receptors in membranes
 Cell permeant
 Lipid soluble
 Steroid hormones
 Cell-associated signaling molecules
 e.g., CAMs ~

Receptor Types
Channel-linked receptors
 Ionotropic
 Enzyme-linked receptors
 Protein kinases mostly
 Neurotrophin-R
 G-protein-coupled receptors
 Metabotropic
 Intracellular receptors
 Activation by cell-permeant signals ~

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 ~
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 ~
G protein: direct control
R
G
GDP
G protein: direct control
R
G
GTP
*
GDP
G protein: direct control
R
G
GTP
Pore
2d Messenger Systems
NT = 1st messenger
 Membrane-associated components
 Receptor
 Transducer
 Primary effector
 Intracellular
 2d messenger
 Secondary effector ~

2d Messenger Targets
Enzymes
 Modulate phosphorylation
 Protein Kinases
2+ , cAMP, DAG, etc.
 activated by: Ca
 Increase phosphorylation
 Protein Phosphatases
 Decrease phosphorylation
2+/calmodulin ~
 activated by Ca

2d Messenger Targets:
Nuclear Signaling
Modulates protein synthesis
 Slow: 30-60 min
 Transcriptional activator proteins
 DNA  RNA  Proteins ~

2d Messenger Systems
Slower & enduring changes
 Multiple effectors
 Signal amplification
 1 NE  1000s cAMP
 1000s cAMP  10,000s phosphates
 Effects
 Control channel
 Alter properties of receptors
 regulation of gene expression ~

2d Messengers
Calcium (Ca2+)
 Target: calmodulin
 Calmodulin  protein kinases &
phosphatases
 Cyclic nucleotides
 cAMP & cGMP
 Target: protein kinases ~

2d Messengers: Membrane Lipids

Precursor: PIP2
Phosphatidylinositol
biphosphate
Cleaved by phospholipase C
 Diacylglycerol
 DAG  Protein Kinase C (membrane)
 Inositol triphosphate
2+ (endoplasmic reticulum) ~
 IP3  Ca

b-adrenergic 2d Messenger System
external signal: nt
norepinephrine
Receptor
b adrenergic -R
transducer
primary
effector
GS
adenylyl
cyclase
2d messenger
cAMP
secondary effector
protein kinase
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 ~

G protein: Protein Phosphorylation
A
C
R
G
GDP
PK
G protein: Protein Phosphorylation
A
C
R
G
ATP
GTP
cAMP
PK
G protein: Protein Phosphorylation
A
C
R
G
ATP
GTP
cAMP
PK
P
G protein: Protein Phosphorylation
A
C
R
G
ATP
GTP
P
cAMP
PK
Pore