Lecture 9 - Signalling Pathways

Question 1

How do extracellular mediators effect the cytosol and nucleus.

Answer 1

Extracellular mediators can cause a diverse number of changes in the cytosol or nucleus
Cytosol: Modifications of cellular metabolism, function, movement
Nucleus: modifications to gene expression and development
The extracellular mediators first need to cross the plasma membrane (signal transduction)

Question 2

How do extracellular signals enter the cell?

Answer 2

Hydrophobic signals such as steroids, retinoids and Thyroxine are able to pass through the plasma membrane where they can bind to a cytosolic receptor where perception takes place followed by a response.

Most extracellular mediators are unable to pass through the phospholipid bilayer so are perceived by cell surface receptors in the plasma membrane. Their binding to these receptors activates them which causes signal transduction protein and second messengers which move the signal to the location in the cell where it is needed. This can involve:
* Enzyme activation
* Enzyme cascade
* Second messenger
* Protein translocation
* Activation of TF

Question 3

Whate are the four stages of cell signalling?

Answer 3

1. Signal
2. Perception
3. Transduction
4. Response

Question 4

What are the three types of signals and extracellular mediators ?

Answer 4

There are three types of cell-cell signalling
* Endocrine - Long range, blood born hormones, Hormones are released from an endocrine gland into the blood where they travel to target cells.
* Paracrine - Short range, localised action growth factors and cytokines, Moves over short distance and is perceived by receptors on the plasma membrane of an adjacent cell.
* Autocrine - Same cell signalling normally growth factors and cytokines, signal is secreted by the cell and is perceived by receptors on the same cell.

Types of extracellular mediators:
* Hormones - Endocrine action, blood borne, short term metabolic effects.
* Growth factors - Paracrine or autocrine action, generally long term proliferation/developmental effects
* Steroid hormone - Intracellular receptors (autocrine action), long term effects

Question 5

What receptors are involved in signal transduction

Answer 5

Receptors involved in signal transduction
* G protein coupled receptors - responsible for short-term changes in cell function - metabolism and movement
* Enzyme coupled receptors
○ Receptors with intrinsic enzyme activity - When activated form dimers and can then phosphorylate. E.g. Receptor serine-threonine kinases and Receptor tyrosine kinases
○ Receptors associated with an enzyme - Long term changes in gene expression or development E.g. Cytokine receptors
* Ion channel receptors (Ligand-gated ion channels) - Ion channels respond to stimulus and allow influx of ions E.g. Transient receptor potential channels

Question 6

What are second messengers?

Answer 6

Second messengers - intracellular metabolite or ion which couples an extracellular stimulus to a physiological response
* It must be small
* Mechanism for inducing rapid alterations in concentration (formation and breakdown)
* Controlled by extracellular stimuli
* Must regulate either an enzymes activity or protein function
* Must involve highly specific interactions
* Amplification must be present in the system

Examples of second messengers
Cyclic nucleotides
3’,5’ Cyclic AMP - Activates protein kinase A causing an increase in lipid breakdown and a decrease in glycogen synthesis
3’,5’ Cyclic GMP - Activates protein kinase G causing cation channels in rod cells to open

Lipid-derived messengers
1,2-diacylglycerol - Activates Protein kinase C which causes a decrease in glycogen synezesis and an increase in transcription
Inositol 1,4,5-triphosphate (IP3) - Opens Ca2+ channels in the endoplasmic reticulum which activates Ca2+ dependent protein kinases

Question 7

Why is kinase activation a frequent response to second messenger increases?

Answer 7

Kinase activation is a frequent response to second messenger increases which effects that activation of additional downstream signalling components through reversible phosphorylation. It is importnaat that phosphorylation of downstream signaling components is reversible and not irreversible phosphorylation as this allows for the signaling pathway to be reset after stimulation. To this end, kinases are paired against protein phosphatases which dephosphorylate the phosphorylated proteins.
The targets for these protein phosphatases are particular amino acid on proteins. Typically, these phosphorylation events occur at tyrosine residues, serine residues, and threonine residues. Therefore, the kinases are referred to as tyrosine, serine and threonine kinases.

Therefore, there are a range of kinases which are targeted by second messengers. The table in this slide, just gives you a very brief overview of some of the signals and the second messengers and how those then affect different enzymes:
· cyclic nucleotides - cyclic AMP-dependent protein kinases; cyclic GMP dependent protein kinase
· Calcium, and calmodulin (calmodulin is a sensor which binds and responds to Calcium) -calcium-calmodulin-dependent protein kinase
· diacylglycerol – protein kinase C