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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

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Signal Transduction

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  1. Signal Transduction Lecture 14

  2. Ligands & Receptors • Ligand • Neurotransmitters & drugs • Receptor proteins • ligand binds to multiple receptors • Binding site • specific point of ligand & receptor • Affinity • attraction • physical & electrical fit~

  3. 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 ~

  4. Chemical Signaling Mechanisms • Synaptic • Paracrine • Medium range intercellular signaling • Endocrine • Hormones via blood • Pheromones • Via air ~

  5. Signaling Pathways • Cell impermeant • Requires receptors in membranes • Cell permeant • Lipid soluble • Steroid hormones • Cell-associated signaling molecules • e.g., CAMs ~

  6. 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 ~

  7. 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 ~

  8. 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 ~

  9. R G GDP G protein: direct control

  10. R G GTP GDP G protein: direct control *

  11. R G GTP G protein: direct control Pore

  12. 2d Messenger Systems • NT = 1st messenger • Membrane-associated components • Receptor • Transducer • Primary effector • Intracellular • 2d messenger • Secondary effector ~

  13. 2d Messenger Targets • Enzymes • Modulate phosphorylation • Protein Kinases • activated by: Ca2+ , cAMP, DAG, etc. • Increase phosphorylation • Protein Phosphatases • Decrease phosphorylation • activated by Ca2+/calmodulin ~

  14. 2d Messenger Targets: Nuclear Signaling • Modulates protein synthesis • Slow: 30-60 min • Transcriptional activator proteins • DNA  RNA  Proteins ~

  15. 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 ~

  16. 2d Messengers • Calcium (Ca2+) • Target: calmodulin • Calmodulin  protein kinases & phosphatases • Cyclic nucleotides • cAMP & cGMP • Target: protein kinases ~

  17. 2d Messengers: Membrane Lipids • Precursor: PIP2 • Phosphatidylinositol biphosphate • Cleaved by phospholipase C • Diacylglycerol • DAG  Protein Kinase C (membrane) • Inositol triphosphate • IP3  Ca2+ (endoplasmic reticulum) ~

  18. Receptor Receptor b adrenergic -R trans- ducer trans- ducer primary effector primary effector adenylyl cyclase b-adrenergic 2d Messenger System external signal: nt external signal: nt norepinephrine GS 2d messenger 2d messenger cAMP secondary effector secondary effector protein kinase

  19. 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 ~

  20. A C R G GDP G protein: Protein Phosphorylation PK

  21. A C R G GTP G protein: Protein Phosphorylation ATP cAMP PK

  22. A C R G GTP G protein: Protein Phosphorylation ATP cAMP P PK

  23. A C R G GTP Pore G protein: Protein Phosphorylation ATP P cAMP PK

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