Physiology 3140A Lecture Notes - Lecture 14: Arachidonic Acid, Adenylyl Cyclase, Inositol Trisphosphate
22 May 2018
School
Department
Course
Professor
Physiology 3140
Dr. Rylett
Lecture 14
Other Lipid derived chemical mediators
Second messengers and mediators derived from membrane lipids
- most lipid-derived mediators are produced from phospholipids PI and PC by phospholipases
- PS does not serve as a good source of some of these other mediators bc PS needs to be sitting on
the PM and intact to be able to attract PKC
- PS role: serve as an attractant and anchor for PKC
o So you don’t want to be chopping up PS or you will have problems with PKC activation
- PE also doesn’t really participate a lot
- So the really important ones are PI and PC
- best characterized is generation of inositol triphosphate (IP3) and diacylglycerol by
phospholipase C-β from PI
- other mediators include:
o they come from arachidonic acid
o mediators with both autocrine and endocrine functions (e.g. prostaglandins and
platelet-activating factor)
▪ autocrine factor:
• its going to act on the cell that makes and releases it
• tells cell that it has completed its job
• ex: hormone needs to be released from that cell to go elsewhere – you
might have an autocrine factor that is co made and co released - it can
come back and bind to receptors on the same cell – tells cell that the
hormone was released and did its job
▪ endocrine/paracrine factor
• short lived and short distance
• ex: NO
• prostaglandins have a larger endocrine effect (mediate effects in cells
that are further away)
Eicosanoids (including prostaglandins)
- large group of compounds including
o prostaglandins
o thromboxanes,
o leukotrienes
o prostacyclins
- within each group there are even more molecules
- all formed from one essential fatty acid: arachidonic acid
o essential meaning you need to get it from your diet – body cant make it
- these molecules are not stored in cell, but made on demand by series of enzymatic steps
following stimulation of cell
o recall: cAMP tends to have a basal amount in the cell (10-7 M)
▪ a lot of molecules are like that – there is a basal amount in the cell
▪ but that concentration is below what is needed to stimulate a biological effect in
the cell
▪ based on the Km or binding affinity of the molecule for its receptor
▪ the concentration that is present basally in the cell is below what is needed to
elicit activation
▪ so the cell has to quickly make a lot of that molecule
find more resources at oneclass.com
find more resources at oneclass.com
▪ so when you get activation of adenylate cyclase, the cAMP levels go from 10-7 to
5x10-7 or even 10-6
o these molecules are different, they are made on demand →this means that arachidonic
acid is not free in the cell - its esterified to membrane lipids (bc if it was free in the cell, it
could be metabolized into these biologically active eicosanoids)
o so tehse eicosanoids are made on demand through a series of enzymatic steps that are
initiated hwen the cell is stimulated by something from extracellular environment
- major determinant of rate of synthesis of eicosanoid is availability of free arachidonic acid
o if there is no arachidonic acid available in the free state, even if cell receives a signal to
create eicosanoids, it wont
- so the first step that has to take place: liberation of arachidonic acid from the
glycerophospholipids by phospholipase A2
- cell receives signal from extracellular environment that is going to try to relay info into cell that
requires the activation of prostaglandin or another eicosanoid
- first thing that must happen is we have to get some ararchidonic acid, bc there is not a free pool
of that in the cell
- so arachidonic acid is esterified to PI or PC in the membrane
- we must get activation of phospholipase A2 bc that is going to be the mehcnaims by which we
are going to liberate the arachidonic acid from the glycerophospholipid
- arachidonic acid is found in cell membranes in lipid bound form, esterified to phospholipids and
unavailable for eicosanoid biosynthesis
- arachidonic acid is normally released from membrane phospholipids by phospholipase A2
- so the cell has to have very good mechanisms for regulating phospholipase A2 – if there was too
much of activation of phospholipase A2 under normal conditions, it would be chopping up the
glycerophopsholipids and releasing arachidonic acid constantly
- the downside to this: you get a lot of eicosanoids being made
- these eicosanoids have a broad spectrum of bioloigical activities
o some are inflammatory molecules
o some can lead to vasoconstriction/vasodilation
- another reason you don’t want high levels of phospholipase A2 activity is bc if you take off one of
those fatty acids, the remaining molecule is lysophospholipid (DETERGENT)
o you don’t want a lot of detergent in your PM bc it can lead to cell lyses
o disrupt and enhance the fluidity of PM so it becomes leaky
PC, PI and sometimes PE are sources of arachidonic acid
- phospholipase A2 releases the fatty acid at C2 of the glycerol, this generates a hydroxyl group at
the end and releases arachidonic acid
- arachidonic acid has 4 double bonds (its
unsaturated) →this makes it flexible and places an
opportunity for enzymes to work with those double
bonds and add oxygens or hydroxyl groups
- due to the double bonds, arachidonic acid can be
subject to oxidation
- the 20C arachidonic acid normally folds into a
hairpin and becomes oxidized to prostaglandin E2
- depending on how it becomes modified with these
double bonds, it will produce a different
eicosanoids
find more resources at oneclass.com
find more resources at oneclass.com
Document Summary
Second messengers and mediators derived from membrane lipids. Most lipid-derived mediators are produced from phospholipids pi and pc by phospholipases. Ps does not serve as a good source of some of these other mediators bc ps needs to be sitting on the pm and intact to be able to attract pkc. Ps role: serve as an attractant and anchor for pkc: so you don"t want to be chopping up ps or you will have problems with pkc activation. Pe also doesn"t really participate a lot phospholipase c- from pi. Eicosanoids (including prostaglandins) large group of compounds including: prostaglandins thromboxanes, leukotrienes, prostacyclins all formed from one essential fatty acid: arachidonic acid. Pc, pi and sometimes pe are sources of arachidonic acid. Due to the double bonds, arachidonic acid can be subject to oxidation the 20c arachidonic acid normally folds into a hairpin and becomes oxidized to prostaglandin e2.
