1. Receptors Lesson 8

2. Ligands & Receptors • Ligand • neurotransmitters • drugs • Receptor proteins • ligand binds to multiple receptors • receptor subtypes • specificity ~

3. 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 ~

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

5. NT Receptor A • ligand binds to receptor • activation: EPSP or IPSP ~

6. NT Receptor A Receptor B • Same NT can bind to different -R • different part of NT ~

7. NT Receptor A Receptor B • Same NT can bind to different -R • different part of NT ~

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

9. 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 ~

10. DRUG NH2 Amphetamine • ligand binding • drug fx ~ RECEPTOR

11. DRUG NH2 Amphetamine • ligand binding • drug fx ~ RECEPTOR

12. DRUG NH2 MDA • Stronger binding • greater fx ~ RECEPTOR

13. DRUG NH MDMA • Stronger binding • greater fx ~ RECEPTOR

14. Drug Interaction Terms • Agonist (AG) • mimics or ­NT effects • Antagonist (ANT) • blocks or ¯NT effects ~

15. 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 ~

16. 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 ~

17. 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 ~

18. NT ANT RECEPTOR ANT NT Antagonists

19. NT RECEPTOR ANT NT Antagonists

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

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

22. R G GDP G protein-gated Ion Channels

23. R G GTP G protein-gated Ion Channels Pore

24. 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 ~

25. 2d Messenger Systems • External signal • NT = 1st messenger • Membrane-associated components • Receptor • Transducer • Primary effector • Intracellular • 2d messenger • Secondary effector ~

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

27. 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

28. A C R G GTP GDP G protein: Protein Phosphorylation * PKA

29. A C R G GTP Pore G protein: Protein Phosphorylation ATP P cAMP PKA