Cell biology lecture 17

Signal pathway regulation

Learning objectives

• How different cells respond differently to the same signal ​

• How signalling pathways interact in a coordinated way​

• How signalling pathways are switched off ​

• How some drugs act by interfering with the “on/off” switch

Coordination of signalling pathways

• Different cells can respond differently to the same signal:​

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• By using different receptors​

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• By activating different intracellular machinery​

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• E.g. Acetylcholine receptors​

• - Skeletal muscle cells (L15)​

• - Heart muscle cells​

• - Endothelial cells (L14)​

• - Pancreatic acinar cells

Nicotinic Ach receptor vs muscarinic Ach receptor

NO and intracellular receptors

Activating different intracellular machinery:​ Pancreatic acinar cell

GPCR

Activating different intracellular machinery:​ Endothelial cell

GPCR

What can signalling pathways do?

They can interact and different responses need diff combinations of signal

Signals may combine to alter the activity of signalling protein​

Signals may combine to alter the activity of signalling protein​

Signals may combine to alter the level of active signalling protein​

what is overlap between signalling pathways known as?

Cross talk

• Common 2nd messengers are shared by many different pathways​

• Some signalling proteins are shared by different pathways

Ad:

allows fine-tuning of response – different signals can act together to control levels of a 2nd messenger or activity of a signalling protein

Dis:

means that there is a risk of a signal producing the wrong response​

Signalling complexes 1

1) Stable: components of the signalling pathway are linked by a scaffold protein​

Signalling complex 

2) Transient: the signalling complex assembles after the receptor is activated​

Signalling complex 3

3) Transient: modification of plasma phospholipid molecules​

Switching the signal off 

Failure to do so can lead to cancer (Ras pathway) or cholera toxin (GPCR)

Need to be switched off to prevent this

Many drugs use this process to solve diseases/dysfunctions

Switching signal off 1

Removal/ inactivation of signal

• By degradation e.g. hydrolysis of acetylcholine by acetylcholinesterase​

• By recycling of signalling molecule e.g. neurotransmitters: serotonin,dopamine​

• By sequestration by other proteins e.g. soluble TNF receptor

Speed of inactivation

Switching off 2 

Removal of receptors 

• Allows cells to become adapted to a constant signal – desensitization​

• A common mechanism is ligand-dependent receptor-mediated endocytosis

Switching off 3 

Inactivation of activated proteins - molecular switches 

Cholera toxin

Interferes with G protein hydrolysis

• ADP-ribosylation of Gα prevents hydrolysis of GTP​

• Locks G-protein in an active state​

• Adenylyl cyclase remains activated​

• Increase in cAMP leads to loss of Cl- and water into intestinal lumen ​

• Severe watery diarrhoea > dehydration > death

Allosteric Inactivation​

Switching off 4 

Degradation/removal of second messengers 

E.g. Removal of cAMP and cGMP by hydrolysis​

• Catalysed by phosphodiesterase

Summary

• How different cells respond differently to the same signal ​

• How signalling pathways interact in a coordinated way​

• How signalling pathways are switched off ​

• How some drugs act by interfering with the “on/off” switch

Lecture series summary 

L14: Principles of cell signalling. Local and distant signalling. Intracellular receptorsignalling. Androgen insensitivity. NO signalling and blood flow. ​

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L15: Ion gated receptors, muscle contraction and Myasthenia gravis. GPCR, trimericG-proteins as transducers. cAMP as second messenger and amplification. ​

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L16: IP3, DAG, Ca2+ and calmodulin. Enzyme-linked receptors, receptor tyrosinekinases, monomeric G proteins, the RAS-MAPK cascades and cancer.​

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L17: Coordination, cross talk and switching signalling off. Cholera, Prozac andViagra.

Lecture series LOs

• Understand the important principles of cell signalling​

• Understand how cells can send signals to each other over short and long distances​

• Describe the differences between intracellular and extracellular receptors​

• Be able to describe some common signalling pathways ​

• Be able to use the pathways you know to illustrate the key principles of cell signalling