Receptors Lesson 8

Ligands & Receptors n Ligand l neurotransmitters l drugs n Receptor proteins l ligand binds to multiple receptors l receptor subtypes l specificity ~

Ligand-Receptors Binding n Binding site l specific point of ligand & receptor n Affinity l attraction l physical & electrical fit n NT or drug binds to receptor l  or  activity of neuron l excite or inhibit n Drugs mimic or block NT message ~

Lock & Key Model n Receptor changes shape n Excitation or Inhibition? l Determined by nature of receptor l receptor subtypes n NOT NT ~ n NT binds to receptor l NT = key l Receptor = lock

Receptor A NT n ligand binds to receptor l activation: EPSP or IPSP ~

Receptor B Receptor A n Same NT can bind to different -R l different part of NT ~ NT

Receptor B Receptor A n Same NT can bind to different -R l different part of NT ~ NT

Receptor B Receptor A NT Specificity of drugs Drug A Drug B

Structure-activity relationship n NT fits receptor site u key & lock n Change structure of drug... l change its affinity u increase or decrease l may bind to different receptor n Behavior mediated by synaptic activity l most drugs act at synapse ~

RECEPTOR DRUG n ligand binding n drug fx ~ Amphetamine NH 2

RECEPTOR DRUG n ligand binding n drug fx ~ Amphetamine NH 2

RECEPTOR DRUG n Stronger binding n greater fx ~ NH 2 MDA

RECEPTOR DRUG n Stronger binding n greater fx ~ MDMA NH

Drug Interaction Terms n Agonist (AG) mimics or  NT effects n Antagonist (ANT) blocks or  NT effects ~

Drug Interaction Terms n Direct agonist l activates receptor n direct antagonist l also binds to postsynaptic receptor l does not activate n Indirect (agonist/antagonist) l affects other parts of synaptic transmission model ~

Drug Interaction Terms n Competitive antagonist l competes for same receptor site l < affinity of NT n Noncompetitive l same binding site, >> affinity than NT l or different binding site on receptor ~

Drug Interaction Terms n Allosteric interactions l At different site, same receptor l noncompetitive antagonism l Potentiation (agonistic) n Partial agonist l activates -R, but weaker than NT n Inverse Agonist l activates receptor l opposite effect of NT ~

RECEPTOR NT Antagonists NT ANT

RECEPTOR NT Antagonists NT ANT

Receptor Types n Ionotropic receptors l NT directly controls channel l fast & transient action l Rapid desensitization u Tachyphylaxis n Metabotropic receptors l G protein-coupled receptors l requires energy: GTP l neuromodulation ~

Metabotropic receptors n G protein-gated Ion Channels l Receptor indirectly controls channel l relatively fast n 2d messenger systems l Effects relatively slow l long-lasting l Signal amplification ~

G protein-gated Ion Channels R G GDP

G protein-gated Ion Channels R G GTP Pore

2d Messenger Effects n Modulate phosphorylation l activation of processes l Protein Kinases   l Protein Phosphatases   n Modulate gene expression l transcriptional factors l DNA  RNA  Proteins l e.g., -R up- or down-regulation ~

n External signal l NT = 1st messenger n Membrane-associated components l Receptor l Transducer l Primary effector n Intracellular l 2d messenger l Secondary effector ~ 2d Messenger Systems

G protein: Protein Phosphorylation Receptor trans- ducer primary effector external signal: nt 2d messenger secondary effector Receptor trans- ducer primary effector external signal: nt 2d messenger secondary effector GSGS norepinephrine cAMP protein kinase A  adrenergic -R adenylyl cyclase

2d Messenger Systems n External signal n Receptor n Transducer n Primary effector n 2d messenger n Secondary effector ~ n Norepinephrine n Beta-adrenergic-R n G s –protein n Adenylyl cyclase n cAMP n Protein Kinase A

G protein: Protein Phosphorylation R G GTP ACAC GDP * PKA

G protein: Protein Phosphorylation R ACAC PKA G GTP ATP cAMP P Pore