Lipids and Cell Membranes 2 Flashcards
How do lipids participate in cell-cell communication mechanisms?
By giving rise to intracellular second messengers.
They also act as precursers for eicosanoids
What are the 6 steps in cell to cell communication?
- Synthesis of signal
- Release of signalling molecule (exocytosis/diffusion/cell to cell contact)
- Transport of signal to target cell
- Detection of signal by specific receptor protein
- A change in cellular metabolism, function or development triggered by receptor-signal complex
- Removal of signal or desensitisation
Give two examples of long-range signals and how they work
Endocrine - hormones released by endocrine cells and carried in blood stream to target cells
Neurotransmitters (long distances because neurons can be very long)
Give two examples of short range signals and how they work
Paracrine - Signalling molecules only affecting target cells in close proximity
Autocrine - Cells respond to substances that they themselves release
Give an example of how multiple types signalling can be occurring simultaneously
Insulin releases can act in an autocrine, paracrine and endocrine manner.
Where can signalling molecules bind? What is most common?
Extracellular receptors - This is most common
Intracellular receptors- Less common and occurs with hydrophobic molecules
What are the different types of receptors? and their time scale
Ligand gated ion channels - milliseconds
G-protein-coupled receptors - seconds
Kinase-linked receptors - hours
Nuclear receptors - hours (longer because it involved time for proteins to be made)
Using cortisol as a specific example, explain how intracellular signalling occurs
Cortisol binds to intracellular receptor in cytosol changing its conformation. The activated receptor then translocated into the nucleus where is binds to a regulatory region of the target gene and activates transcription.
What is PIP(2)? (small two) and what is it a substrate for?
A phospholipid found in the lipid bilayer called Phosphotidylinositol 4,5-bisphophate. It is a substrate for the enzyme phospholipase C (PLC)
What is the function of Phospholipase C? (PLC)
It cleaves PIP(2) into two products; Inositol 1,4,5 triphosphate (IP(3)) and Diacyglycerol (DAG)
How is Protein Kinase C (PKC) activated?
PIP(2) is cleaved into IP(3) and DAG by PLC. The IP(3) opens calcium channels in the endoplasmic reticulum which binds to domain C2 causing it to trans-locate to the cell membrane where DAG binds to the C1 domain causing a conformational change and activating the enzyme.
With IP(3) release, what happens to calcium levels?
They greatly increase and since calcium is used to regulate protein function this is very important
What are some substrates for PKC (Protein Kinase C)
Tumour suppressor p53 - prevents tumor formation.
Ca(v) 1.2 - heart muscle contraction.
Cytokine - activates B cells
After signal transduction, what occurs to IP(3)
it is recycled and returned to the membrane as PIP(2)
What are Eicosanoids and what are some of their features?
- They are inflammatory mediatiors
- Considered local hormones as they act on cells close to their site of formation, as they are rapidly degraded.
What are the principle Eicosanoids?
Prostoglandins, thromboxanes and leukotrienes
What is the initial and rate-limiting step in eicosanoid formation?
The liberation of arachidonic acid from phospholipids by phospholipase A2 (PLA(2))
Where does Phospholipase A2 (PLA(2))cleave the fatty acid?
On the second chain of a fatty acid
What is PLA(2) activated by?
Seratonin receptors, glutamate receptor 1, some cytokine receptors and increase in calcium concentrations.
Describe what products form from the breakdown of phospholipids by Phospholipase A2 (PLA(2))
Platelet activating factor (PAF) and arachidonic acid
Arachidonic acid can be metabolised by what?
- Cyclo-oxygenase and peroxidase to form prostaglandins and thromboxanes
- Lipoxygenase to give leukotrienes
What are prostaglandins involved in?
Vasoconstriction/dilation
Inhibit/promote platelet aggregation (depends on receptors), Inflammatory response, thermoregulation and pain.
Where are prostoglandins synthesised?
In all tissue and cell types
Where are thromboxanes synthesised in?
Platelets
What is thromboxanes involved in?
Platelet aggregation and vasoconstriction
Where are leukotrienes synthesised?
White blood cells
What are leukotrienes involved in?
The immue response and are heavily involved in asthma and allergies. Have amino acid cysteine which is linked to anaphylactic shock
What is platelet activating factor involved in? and what is it produced by?
Produced by injured tissue and leukocytes. It is involved in;
Platelet aggregation, vasoconstriction, inflammation and immune response
What do non-steroidal anti-inflammatory drugs inhibit? and name exampls of the drugs
They inhibit cyco-oxygenase which in turn inhibits formation of prostaglandins involved in fever, pain and inflammation and also inhibit blood clotting by blocking thromboxane formation in blood platelets. Examples of NSAID’s are aspirin and ibuprofen
Explain how aspirin inhibits formation of prostaglandins
It acetylates with a serine hydroxyl group near active site preventing arachidonic acid from binding. This is irreversible but formation of more cyclooxygenases would restore their activity.
Explain how aspirin acts as an anticoagulant
It inhibits thromboxane formations via cyclo-oxygenase inhibition in blood platelets. The effect is long lived as platelets lack a nucleus so do not make new enzymes.
