Signal Transduction: Ligand-Receptor Interactions Cell and Developmental Biology Group

1. Signal Transduction: Ligand-Receptor Interactions Cell and Developmental Biology Group

2. Goals – Integration of quantitative skills in cell biology Modeling cellular responses

3. Class setup • First or second year majors in cell biology • Co-requisite with Calculus • Middle of the course • ~1 hour lecture Learning outcomes 1) Relate the concept of threshold to cellular responses 2) Understand how these components affect threshold - ligand and receptor concentrations - binding affinity 3) Apply knowledge of quantitative models of cellular response

4. A driver returned to his car after a 3 hour shopping spree to see the following sight. His car would not start. Why?

5. Draw how the battery / ignition threshold would look on this graph ignition Response (ignition) No ignition Battery current low high

6. Cell Signaling EXTRACELLULAR FLUID CYTOPLASM Plasma membrane Reception Transduction Response Receptor Activation of cellular response Tomorrow’s presentation Relay molecules in a signal transduction pathway Signal molecule

7. What happens when you see this?

8. Effects of adrenaline on different tissues in the body

9. Threshold as it relates to ligand receptor binding and cellular function Maximum response threshold Reception Fight - Flight response Basic response threshold [Adrenaline] Ligand / receptor concept low high

10. Binding Affinity k1 • [L] + [R] [LR] • Dissociation Constant (Kd): is the free ligand concentration at which 50% of receptor is occupied. • Affinity is defined by the association constant (Ka ) =1/Kd • Each ligand / receptor complex has its own specific binding affinity. Kd = k-1 / k1 k-1

11. Which graph represents a cell with a receptor with the highest affinity? A response B C D [ligand] low high

12. (Think-Pair  1 minute essay) What is the relationship between affinity and threshold? response A B C D [ligand] low high

13. Affinity and the curves • Associate each of the following with the appropriate graph above • A. [L]=1 µM, [R]=0.5 µM, Kd=.25 µM • [L]=1 µM, [R]=1.25 µM, Kd=.25 µM Response Affinity = 1 / Kd B A [Ligand]

14. Affinity and the curves • Associate each of the following with the appropriate graph above • A. [L]=1 µM, [R]=1.25 µM, Kd=.25 µM • B. [L]=1 µM, [R]=1.25 µM, Kd=.5 µM Response Affinity = 1 / Kd A B [Ligand]

15. Relationship between [R],[LR],Kd In general, • What happens to [LR] when [R] increases and Kd stays the same? • What happens to [LR] when Kd increases and [R] stays the same?

16. What happens when your adrenaline rush goes away??

17. Off-switch (negative threshold) Maximum response threshold Fight - Flight response Basic response threshold [Adrenaline] low high

18. Ligand-receptor interactions are widespread and have varied roles in organisms. Development Environmental sensing The immune system

19. Summative Assessment • Explain the concept of threshold • Relate changes in dissociation constants to cellular responses • Correlate changing Kd values to how they affect the graph 3) Describe the effects that drug A would have on the fight or flight response if drug A: • Lowered the concentration of adrenaline • Blocked the receptor 4)Relate the importance of understanding mathematics to experimentally analyzing cellular responses