1. Signal Transduction Lecture 14

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

3. Receptor Activation n Lock & Key Model n Structure-activity relationship l Physical & electrical fit l Affinity n Activation  excitation or inhibition n Drugs l Change structure  change affinity l Agonists  activate l Antagonists  no activation ~

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

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

6. Receptor Types n Channel-linked receptors l Ionotropic n Enzyme-linked receptors l Protein kinases mostly l Neurotrophin-R n G-protein-coupled receptors l Metabotropic n Intracellular receptors l Activation by cell-permeant signals ~

7. Metabotropic receptors n G protein-coupled receptors l requires GTP n Receptor indirectly controls channel l G protein-gated ion channels l 2d messenger systems n neuromodulation l slower action l changes in sensitivity of neuron ~

8. G protein-gated Ion Channels n NT binds to receptor protein l activates G protein n G protein binds to channel l opens or closes l relatively fast u compared to 2d messenger systems ~

9. G protein: direct control R G GDP

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

11. G protein: direct control R G GTP Pore

12. n 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

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

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

15. 2d Messenger Systems n Slower & enduring changes l Multiple effectors n Signal amplification l 1 NE  1000s cAMP l 1000s cAMP  10,000s phosphates n Effects l Control channel l Alter properties of receptors l regulation of gene expression ~

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

17. 2d Messengers: Membrane Lipids n Precursor: PIP 2 u Phosphatidylinositol biphosphate l Cleaved by phospholipase C n Diacylglycerol l DAG  Protein Kinase C (membrane) n Inositol triphosphate l IP 3  Ca 2+ (endoplasmic reticulum) ~

18.  adrenergic 2d Messenger System 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  adrenergic -R adenylyl cyclase

19.  adrenergic 2d Messenger System n NT: Norepinephrine n Membrane-associated components Receptor:  adrenergic l Transducer: G s protein l Primary effector: Adenyly cyclase n Intracellular components l 2d messenger: cAMP l Secondary effector: Protein kinase ~

20. G protein: Protein Phosphorylation R G GDP ACAC PK

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

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

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