12 - Generation of Lipid Derived Hormones Flashcards
Role of phospholipase A2 (PLA2)
*PLA2 has a major role in signal transduction as it releases arachidonic acid (AA C20H32O2), which serves as a precursor to the biosynthesis of prostaglandins, thromboxanes, leukotrienes, and other eicosanoids
How is arachidonic acid synthesised?
AA is synthesised in cells from linoleic acid, an essential fatty acid
o We can synthesis AA de novo, we need to eat linoleic acid
Pathway to arachidonic acid
Linoleic acid –> gamma linoleic acid –> dihomo gamma linoleic acid –> arachidonic acid
What needs to happen before AA can be converted into signalling molecules?
AA must be released from the plasma membrane before it can be converted into signalling molecules and this is the rate limiting step
What allows the release of AA?
o There are a number of cell surface receptors that allow the release of AA, this includes g protein coupled receptors, tyrosine kinase coupled receptors and ion coupled receptors
- these activate the ERK MAP kinase cascade
- this phosphorylated and activates phospholipase A2 which then acts of the glycerol phospholipids and cleaves them to release AA
What are the two major AA pathways?
The cyclooxygenase pathway and the lipoxygenase pathway
What does the cyclooxyrgenase pathway involve?
The C pathway involves enzymes: COX1 and COX2
* Produces prostaglandins, thromboxane, and prostacyclin
* The intermediator is prostaglandin H2
What does the lipoxygenase pathway involve?
The L pathway involves the enzyme 5-LO
* Intermediatory is leukotrieneA4 which is then converted into leukotrienes
What does phospholipase A2 release?
Phospholipase A2 also releases lysophosphatidylcholine which is converted into platelet activating factor (involved in blood clotting cascade)
What are leukotrienes produced by and involved in?
Leukotrienes are produced by cells of the immune system and are involved in asthmatic and allergic reactions by sustaining inflammatory reactions
Where are the enzymes that covert AA into leukotrienes?
The immune system cells have the enzymes that can convert AA into leukotrienes
What is asthma involved in?
Asthma is involved in the constriction of the lungs- the bronchi is constricted due to smooth muscle action
What do leukotrienes affect?
Leukotrienes have a powerful effect on vasoconstriction and bronchoconstriction, they also increase vascular permeability
o Vascular permeability is when the lining of the blood vessels open up to allow immune cells to access
o Bronchoconstriction is undesirable
What is used to treat asthma?
Several leukotriene receptor antagonists are used to treat asthma (act on GCPRs)
o Block the action of leukotrienes and prevent bronchoconstriction borugh about by leukrotrienes
Give some examples of leukotrienes
Examples of leukotrienes are LTA4, LTB4, LTC4, LTD4, LTE4, and LTF4
What is the function of prostaglandins?
Prostaglandins exert only a paracrine (locally active) or autocrine (acting on the same cell form which it is synthesised) function
Effectiveness of prostaglandins
They are potent but have short half life before being activated and excreted
o Quite unstable, activated quickly then excreted
How many known prostaglandins are there?
There are currently nine known prostaglandin receptors on various cell types
What do prostaglandins act on?
Prostaglandins act on a subfamily of cell surface seven-transmembrane receptors. G-protein coupled receptors (GPCRs)
o GPCRs. Elevate cyclic AMP in target cells
Prostaglandins act on a variety of cells, including platelets, endothelium, uterine and mast cells, and have a wide variety of actions
Give examples of actions of prostaglandins
o Dilation in vascular smooth muscle cells (lower blood pressure)
o Platelet aggregation
o Sensitise spinal neurons to pain
o Constrict smooth muscle (e.g. uterine)
- Used for delayed labour as a gel
o Regulate inflammatory mediation
o Regulate calcium movement
o Regulate hormone action
o Control cell growth
What are thromboxanes?
Thromboxanes are vasoconstrictors and potent hypertensive agents
What is thromboxane A2 produced by?
Thromboxane A2 (TXA2) is produced by activated platelets and facilitates platelet aggregation
o Thromboxanes are produced at the wound site causing platelet to clot and causes vasoconstriction limiting bleeding
What does aspirin do?
Aspirin inhibits cyclooxygenase (COX) enzyme preventing synthesis of thromboxane within platelets
o Aspirin covalently modifies the COX enzyme
What does aspirin act as?
- Aspirin can therefore act as an anti-hypertensive because it can relieve vasoconstriction and prevents thrombosis
- Aspirin acts as a painkiller and an anti-hypertensive (2 role)
Physiological stimulus of PLA2
Physiological stimulus: COX1 is generally involved in normal physiological processes (basal level), involved in homeostasis
o Acts on AA to produce thromboxane (platelet aggregation, vasoconstriction), PGI2 (vasodilation, GI mucosal protection) and PGE1/2 (kidney, GI tract, CNS)
Inflammatory stimulus of PLA2
Inflammatory Stimulus: COX 2 acts more on AA, conversion of AA into prostalgadin E2 at the site of wounding or infection, causes pain sensitisation and vasodiliation and other inflammatory responses to allow immune cells into the site of inflammation
What does paracetamol act on?
Paracetamol is a good anti-inflammatory and pain killer, it blocks the action of COX2, therefore reducing pain and inflammation as it blocks the production of PGE2
What does aspirin act on?
Aspirin acts on COX1 and COX2, anti inflammatory and anti-thromboxin
