Signal Transduction:Ligand-Receptor Interactions

Cell and Developmental Biology Group

Goals – Integration of quantitative skills in cell biology

Modeling cellular responses  

Class setup• First or second year majors in cell biology• Co-requisite with Calculus• Middle of the course• ~1 hour lecture

Learning outcomes1)  Relate the concept of threshold to cellular responses2)  Understand how these components affect threshold

- ligand and receptor concentrations- binding affinity

3)  Apply knowledge of quantitative models of cellular response

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

Draw how the battery / ignition threshold would look on this graph

Battery current

Response 

(ignitio

n)

low high

No ignition

ignition

Cell SignalingEXTRACELLULARFLUID

Reception

Receptor

Signalmolecule

Plasma membrane

Transduction

CYTOPLASM

Relay molecules in a signal transductionpathway

Response

Activationof cellularresponse

Tomorrow’s presentation

What happens when you see this?

Effects of adrenaline on different tissues in the body

Threshold as it relates to ligand  receptor binding and cellular function

Basic response threshold

Maximum response threshold

[Adrenaline]

Fight - Flight 

response

low highLigand / receptor concept

Reception

Binding Affinity

• [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.

k1

k-1Kd = k-1 / k1

[ligand]

response

Which graph represents a cell with a receptor with the highest affinity? 

low high

A

B C D

(Think-Pair  1 minute essay)

What is the relationship between affinity and threshold?

[ligand]

response

low high

A B C D

Affinity and the curves

 

[Ligand]

Response

dRLLR K/]][[][

Affinity = 1 / Kd

Associate each of the following with the appropriate graph above  A. [L]=1 µM, [R]=0.5 µM, Kd=.25 µM B. [L]=1 µM, [R]=1.25 µM, Kd=.25 µM

B A

Affinity and the curves

 

[Ligand]

Response

dRLLR K/]][[][

Affinity = 1 / Kd

Associate each of the following with the appropriate graph aboveA.  [L]=1 µM, [R]=1.25 µM, Kd=.25 µMB.  [L]=1 µM, [R]=1.25 µM, Kd=.5 µM

A B

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?

What happens when your adrenaline rush goes away??

Off-switch (negative threshold)

Basic response threshold

Maximum response threshold

[Adrenaline]

Fight - Flight 

response

low high

Ligand-receptor interactions are widespread and have varied roles in organisms.

The immune system

Development

Environmental sensing

Summative Assessment

1) Explain the concept of threshold2) 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