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 proteinactivates G protein

G protein binds to channelopens or closesrelatively fast

compared to 2d messenger systems ~

G protein: direct control

RG

GDP

G protein: direct control

RG

GTP

GDP*

G protein: direct control

RG

GTP

Pore

NT = 1st messenger Membrane-associated components

Receptor Transducer Primary effector

Intracellular 2d messenger Secondary effector ~

2d Messenger Systems

2d Messenger Targets

Enzymes Modulate phosphorylation

Protein Kinases activated by: Ca2+ , cAMP, DAG, etc. Increase phosphorylation

Protein Phosphatases Decrease phosphorylation activated by Ca2+/calmodulin ~

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

IP3 Ca2+ (endoplasmic reticulum) ~

adrenergic 2d Messenger System

Receptor

trans-ducer

primaryeffector

external signal: nt

2d messenger

secondary effector

Receptor

trans-ducer

primaryeffector

external signal: nt

2d messenger

secondary effector

GS

norepinephrine

cAMP

protein kinase

adrenergic -R

adenylylcyclase

adrenergic 2d Messenger System

NT: Norepinephrine Membrane-associated components

Receptor: adrenergic Transducer: Gs protein Primary effector: Adenyly cyclase

Intracellular components 2d messenger: cAMP Secondary effector: Protein kinase ~

G protein: Protein Phosphorylation

RG

GDP

AC

PK

G protein: Protein Phosphorylation

R

AC

PK

G

GTPATP

cAMP

G protein: Protein Phosphorylation

R

AC

PK

G

GTPATP

cAMPP

G protein: Protein Phosphorylation

R

AC

PK

G

GTPATP

cAMP

P

Pore