MW L3 Eicosanoids Flashcards
Where do Eicosanoids come from?
3
Oxidation products of 20C fatty acids
(-arachidonic acids
-dihomo gamma-linolenic acid
-eicosapentaenoic)
4 Classical eicosanoids
prostaglandins
prostacyclins
thromboxanes
leukotrienes
4 non-classical eicosanoids
lipoxins
resolvins
isoprostanes
endocannabinoids
What receptor type is for prostaglandins?
specific GPCRs for different prostaglandins
What are the receptors PGE2?
EP1-EP2
What is the receptor for PGI2?
IP
EP2 and IP are couple to……
and do?
Gs coupled (adenylyl cyclase -> increase cAMP)
What are the PGD2 receptors
DP1 and DP2
What is the thromboxane receptor
TP
What is the PGF2 receptor? and what is it coupled to?
FP Gq coupled (PLC -> IP3 and Ca)
Which EP receptor is proinflammatory and which is anti inflammatory
EP2 is potentially anti AND proinflammatory?!!
Is the TP receptor pro or antiinflammatory?
pro-inflammatory
What cells does EP3 activate?
leukocytes
Prostaglandins sensitise ……. and cause increased pain response of ………..
C fibres
bradykinin
EP1 and IP are found in ……. and knock-out of these mice have ………
dorsal root ganglia
no EP1 and IP = decreased pain inflammatory response
PGs cause fever by
elevation of the thermoregulatory set point.
Regulated by production and action of PGE2 in the anterior hypothalamus
What leads to a fever insensitive to NSAIDs and paracetamol?
cerebrovascular injection of PGE2
role of the EP3 receptor
…………..% homology between COX 1 and 2
60%
Critical residue on COX 1 and 2
COX-1 I-523
COX-2 V-523
Both COX 1 and 2 are ……..dimers found on the ………………….
homodimers
found on the inner membrane of the ER
2 components of the COX
peroxidase site
cyclooxygenase site
How does aspirin work on cox?
acetylates the serine residue (530 in COX1 and 516 in COX 2)
the COX pocket where inhibitors bind are hydrophobic or hydrophilic?
1 or 2 has more space?
Hydrophobic
pocket has more space on COX 2
COX-1 produces what functions?
Homeostatic functions (In GI, renal, platelet, macrophage differentiation)
COX-2 produces what functions?
Inflammation
What is the effect of Glucocorticoids on COX?
Inhibit COX-2
What is the effect of growth factors on COX?
Stimulate COX-2
e.g. of COX 1 selective NSAID
low dose asp
e.g. of mixed COX 1 and 2 NSAID?
diclofenac, asp etc
e.g. of COX-2 selective NSAID (4)
Meloxicam
nimesulide
celecoxib
rofecoxib
5 functions of PGs
- labour
- GI screstio
- inhibit platelet aggregation (& vasodilation)
4 platelet aggregation (% vasoconstriction)
s.e. of nonselective NSAIDS?
GI irritation and bleeding due to COX1 inhibition - thus reducing cytoprotective effects of PG
s.e. rofecoxib?
3.9x increased incidence of thrombotic events
Why is there an increase in thrombotic events?
Endothelial PGI2 derived mainly from COX-2 - suppressed
No effect on platelet COX-1
therefore unbalanced PGI v TXA2 production
Aspirin irreversibly acetylates COX so why is PGI2 still released?
Cells make new COX
PGI is still released
Aspirin irreversibly acetylates COX, why is TXA2 no longer released?
new receptors not made because TXA2 production is in anucleate platelets (days until new produced)
Long term aspirin is also thought to help with
Colon and rectal cancer
AD
Pathway for Leukotriene production?
AA into 5 HPETE (via 5-lipoxygenase)
into LTA2
role of LTB4?
Receptor?
chemotactic
BLT receptor
2 branches of leukotrienes made from LTA2?
LTB4
and
LTC4 -> LTD4 -> LTE4
receptor for LTC4 and derivatives?
2 functions?
cysLT receptor
- bronchoconstriction
- increase vascular perm
……… and ……. are 1000x more potent than Histamine at bronchoconstriction
LTC4 and LTD4
LTC4 and LTD4 stimulate vascular …………(neutrophil independent)
and
LTB4 increases vascular…………………. (neutrophil dependent)
permeability
Chemotaxis is caused by activation of the …………….. receptor
BLT
Leukotrienes cause inflammation, high levels found in
RA synovial fluid
Glucocorticoids inhibit .................... (2) and induce (1)
PLA2 (by inhibiting transcription)
& COX 2 synthesis
and induce endogenous PLA2 inhibitor
5-lipoxygenase inhibitor
zileuton
LTC4 and LTD4 inhibitors
zafirlukast
montelukast
3 things that eicosanoids synergise with?
hist
brady
chemotaxins
