Receptors

Lesson 8

Ligands & Receptors Ligand

neurotransmitters drugs

Receptor proteins ligand binds to multiple receptors receptor subtypes specificity ~

Ligand-Receptors Binding Binding site

specific point of ligand & receptor Affinity

attraction physical & electrical fit

NT or drug binds to receptor or activity of neuron excite or inhibit

Drugs mimic or block NT message ~

Lock & Key Model

Receptor changes shape Excitation or Inhibition?

Determined by nature of receptor receptor subtypes

NOT NT ~

NT binds to receptor NT = key Receptor = lock

Receptor A

NT

ligand binds to receptor activation: EPSP or IPSP ~

Receptor BReceptor A

Same NT can bind to different -R different part of NT ~

NT

Receptor BReceptor A

Same NT can bind to different -R different part of NT ~

NT

Receptor BReceptor A

NT

Specificity of drugs

Drug A Drug B

Structure-activity relationship

NT fits receptor site key & lock

Change structure of drug... change its affinity

increase or decrease may bind to different receptor

Behavior mediated by synaptic activity most drugs act at synapse ~

RECEPTOR

DRUG

ligand binding drug fx ~

Amphetamine

NH2

RECEPTOR

DRUG

ligand binding drug fx ~

Amphetamine

NH2

RECEPTOR

DRUG

Stronger binding greater fx ~

NH2

MDA

RECEPTOR

DRUG

Stronger binding greater fx ~

MDMA

NH

Drug Interaction Terms

Agonist (AG) mimics or NT effects

Antagonist (ANT) blocks or NT effects ~

Drug Interaction Terms

Direct agonist activates receptor

direct antagonist also binds to postsynaptic receptor does not activate

Indirect (agonist/antagonist) affects other parts of synaptic

transmission model ~

Drug Interaction Terms Competitive antagonist

competes for same receptor site < affinity of NT

Noncompetitive same binding site, >> affinity than NT or different binding site on receptor ~

Drug Interaction Terms Allosteric interactions

At different site, same receptor noncompetitive antagonism Potentiation (agonistic)

Partial agonist activates -R, but weaker than NT

Inverse Agonist activates receptor opposite effect of NT ~

RECEPTOR

NT Antagonists

NT

ANT

ANT

RECEPTOR

NT Antagonists

NT

ANT

Receptor Types Ionotropic receptors

NT directly controls channel fast & transient action Rapid desensitization

Tachyphylaxis Metabotropic receptors

G protein-coupled receptors requires energy: GTP neuromodulation ~

Metabotropic receptors G protein-gated Ion Channels

Receptor indirectly controls channel

relatively fast 2d messenger systems

Effects relatively slow long-lasting Signal amplification ~

G protein-gated Ion Channels

RG

GDP

G protein-gated Ion Channels

RG

GTP

Pore

2d Messenger Effects

Modulate phosphorylation activation of processes Protein Kinases Protein Phosphatases

Modulate gene expression transcriptional factors DNA RNA Proteins e.g., -R up- or down-regulation ~

External signal NT = 1st messenger

Membrane-associated components Receptor Transducer Primary effector

Intracellular 2d messenger Secondary effector ~

2d Messenger Systems

G protein: Protein Phosphorylation

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 A

adrenergic -R

adenylylcyclase

2d Messenger Systems

External signal Receptor Transducer Primary effector 2d messenger Secondary effector ~

Norepinephrine Beta-adrenergic-R Gs –protein Adenylyl cyclase cAMP Protein Kinase A

G protein: Protein Phosphorylation

RG

GTP

AC

GDP*

PKA

G protein: Protein Phosphorylation

R

AC

PKA

G

GTPATP

cAMP

P

Pore