Lecture Notes for Chapter 10 Signaling

1. Essential Biochemistry Third Edition Charlotte W. Pratt | Kathleen Cornely Lecture Notes for Chapter 10 Signaling

2. KEY CONCEPTS: Section 10-1 • Receptor-ligand binding is described in terms of a dissociation constant. • G protein-coupled receptors and receptor tyrosine kinases are the two major types of receptors that transduce extracellular signals to the cell interior. • Regulatory mechanisms limit the extent of signaling.

3. Extracellular signals can take on many forms.

4. A ligand binds to a receptor with a characteristic affinity (Kd). Units:Molarity • Kd = [Ligand] when the receptor is half-saturated. • Low values of Kd indicate strong binding (high affinity).

5. Receptor-ligand binding is hyperbolic.

6. A ligand that binds to a receptor and elicits a biological effect is an agonist. Antagonist of Adenosine Receptor – Caffeine binds but does NOT elicit a response Natural agonist for Adenosine Receptor

7. Most signaling occurs through two types of receptors. • G proteins • Kinases

8. Most signaling occurs through two types of receptors. • G proteins • Kinases

9. KEY CONCEPTS: Section 10-2 • Ligand binding to a G protein-coupled receptor alters its conformation so that an intracellular G protein becomes activated. • The G protein stimulates adenylatecyclase to produce the second messenger cAMP, which activates protein kinase A. • G protein-dependent signaling is limited by several mechanisms. • The phosphoinositide signaling system activates a G protein, which leads to the production of lipid-derived second messengers and the activation of protein kinase C. • Cross-talk results when signaling pathways share components.

10. G protein receptors contain seven transmembrane helices. Physiological ligands for the β-adrenergic receptor

11. GPCRs bind to and activate a G protein. Complex Receptor G Protein G Protein with GDP (orange) bound

12. The G Protein Cycle Signaling is limited by the GTPase activity of the α subunit

13. A major target of activated G protein is adenylate cyclase.

14. cAMP activates Protein Kinase A. PKA R = Regulatory subunit C = Catalytic subunit • The level of cAMP determines the level of activity of PKA.

15. The Structure of Protein Kinase A Zoomed in view of active site

16. Signaling pathways are also switched off.

17. Arrestin reduces a GPCR’s ability to activate a G protein.

18. The phosphoinositide signaling pathway generates two second messengers.

19. Calmodulin mediates some Ca2+ signals. Ca2+ Calmodulin has an extended shape. Calmodulin wraps around its protein target!

20. KEY CONCEPTS: Section 10-3 • Ligands such as insulin activate the tyrosine kinase activity of their receptors. • Receptor tyrosine kinases trigger cellular responses by phosphorylating target proteins and by activating Ras.

21. The insulin receptor has two ligand-binding sites.

22. Insulin receptor tyrosine kinase undergoes autophosphorylation. Light blue = inactive receptor Dark blue = activation loop Light green = active receptor Dark green = activation loop • A conformational change occurs to facilitate autophosphorylation.

23. Ras is active as long as GTP is bound to it.

24. KEY CONCEPTS: Section 10-4 • Lipid hormones bind to intracellular receptors that regulate gene expression. • Eicosanoids are local mediators that act through G protein-coupled receptors.

25. Some hormones are lipids that do not bind to receptors.

26. Some receptors are transcription factors. The Glucocorticoid Receptor-DNA Complex

27. Arachidonate gets converted to eicosanoid signaling molecules.

28. Aspirin inhibits cyclooxygenase. • Prostaglandin synthesis is inhibited, thereby reducing pain.