Lecture 18 Flashcards
(36 cards)
What are eicosanoids, and what is one important process that they are involved in? Where was the first members of this family derived from?
Eicosanoids are a large family of molecules derived from derived from 20 carbon fatty acids. The first member of this family was isolated from semen.
What type of signaling do these molecules act through, and what cells do they act on?
Essentially, eicosanoids are going to be autocrine (in which they act on the cell that secreted them), or they are going to be paracrine (in which they act within a local environment).
Eicosanoids participate in most, if not all ____ pathways.
Eicosanoids participate in most, if not all endocrine pathways.
Essentially, they have a lot of different things that they play a role in because there are a lot of eicosanoids
Eicosanoids play a huge role in _____ and ____ _______ in many tissues.
Eicosanoids play a huge role in pain and pain perception. This is because many, many tissues have the ability to perceive pain (eicosanoids cause inflammation, and pain can be caused by inflammation).
What role do eicosanoids serve in the uterus? What about in platelets and in blood vessels?
In the uterus, eicosanoids play a role in implantation (of fertilized egg) as well as contraction of the uterus (during labor). Eicosanoids are responsible for causing both an increase and a decrease in aggregation of platelets. Eicosanoids are also able to cause vasodilation of blood vessels.
What are the clinical uses synthetic prostaglandins (subclass of eicosanoids)?
- induce childbirth or for abortion
- prevent malformation of the heart in newborns
- Treat and prevent stomach (peptic) ulcers
- Vasodilate for severe limb diseases (helps with circulation)
- Treat pulmonary hypertension
- Treat glaucoma
- Treat erectile dysfunction
- Help eyelashes and eyebrows grow
What are prostaglandins? What processes do they control/play a role in?
Prostaglandins (PGXn) are groups of lipids involved in injury and illness (essentially the molecule that you want to think about when you think about inflammation). Prostaglandins play a huge role in inflammation, blood flow, formation of blood clots, sensitizing the spinal cords to pain, as well as induction of labor.
Are prostaglandins secreted from a gland?
No, prostaglandins are not secreted from a gland to be carried through the blood stream and work on target tissues. Prostaglandins are made/secreted from all of your cells (made through chemical reactions locally and released locally - autocrine/paracrine signaling molecules made by nearly all cells).
The reason why pain is localized within a specific reason is because of this - because these molecules are local acting molecules (made by any cell that needs to make it).
Are prostaglandins short lived or prolonged signaling molecules?
Prostaglandins are rapidly degraded, as these molecules have potent effects. The reason they need to be rapidly degraded is because they are so potent, and because your body does not want these molecules to be dispersed where they do not need to be
Does each different type of prostaglandin affect only one type of receptor and lead to only one different kind of response?
Different receptors for a particular prostaglandin may activate different signaling pathways, and the effect may vary in different tissues (depending on which receptors are expressed).
Explain the structures of PGA, PGE, and PGF with words. What does the 2 in PGE2 indicate?
PGA: this structure has a carbonyl/ketone at the top of the five membered ring, as well as a double bond on the left hand side of the 5 membered ring.
PGE: this structure retains is carbonyl/ketone at the top of the five membered ring (similar to PGA), but has lost the double bond (there is now a hydroxyl group at the bottom of the five membered ring).
PGF: this structure is similar to PGE, however the carbonyl has been reduced to an alpha hydroxy group (which is in the alpha position).
The 2 in PGE2 indicates that there is two double bonds present in the side chains groups.
What does the 3 in PGX3 mean?
Where does this part of the structure originate from? Does each prostaglandin originate from the same source?
PGX3 indicates that this specific prostaglandin has three double bonds total in its side chains (combined total of three double bonds, not three double bonds in each side chain).
What does prostacyclin do, and what hormone has an opposite role to this hormone?
Prostacyclin is a very short acting eicosanoid which is involved in inhibiting platelet activation during hemostasis after the platelet plug has been formed. The reason it is important that it is very short acting is because this should only act locally. Platelets are really important for stopping you from bleeding. You do not want the platelets to be overactive and aggregate too much. Therefore, prostacyclin inhibits further activation of the platelets such that you don’t form unwanted aggregation of platelets (leading to blood clots.) Prostacyclin has an opposite role to thromboxane, which is a potent hypertensive agent and blood clotting agent
Why have analogues to prostacyclin been produced such that their half lives in the body are much longer than prostacyclin normal half life?
First, the reason that prostacyclin has a short half life (42 seconds) is because it acts locally - not all over the body. This is an important characteristic of eicosanoids. However, if someone has an issue where their blood clots too much, or if they have issues with prostacyclin, taking drug analogues to prostacyclin might be beneficial because they would be much more effective and cause a more widespread response.
What do leukotrienes do, and what are they made from? What happens as a result of an overproduction of leukotrienes?
Leukotrienes are involved in immune system regulation - they are responsible for triggering contractions in smooth muscles lining the bronchioles (in the lungs); contractions of the bronchioles are helpful for breathing. Leukotrienes are made by leukocytes. Overproduction of leukotrienes (since they are important in contractions in the smooth muscles lining the bronchioles in the lungs) causes inflammation in bronchioles in the cases of asthma and allergic rhinitis (hay fever). Inflammation of the bronchioles can cause them to not contract properly or over contract, which can stop your ability to breath properly
What are the roles of lipoxins?
Lipoxins are short lived signals which are important in the immune system for anti-inflammatory responses. Their appearance in inflammation signals the resolution of inflammation. As part of the recovery process, these lipoxins will come in to resolve the inflammation
What is one reason that essential fatty acids are important?
Essential fatty acids are required for the production of specific types of eicosanoids. These are essential in your immune function, signaling, and your pain response. Essentially, through a multistep process involving desaturases and elongases, essential fatty acids can be converted into these important hormones.
Arachidonic acid, which is present in cell membranes, is important for the synthesis of different types of eicosanoids, including really important prostaglandins.
How is arachindonic acid liberated from the cell membrane, and how is this process activated? What enzyme is required to produce the prostaglandins?
In order to liberate arachidonic acid from the cell membrane, phospholipase A2 is going to be activated such that it can cut the arachadonic acid away from molecules that are holding it in the cell membrane.
1) A specific stimulus (pain, damage to tissue, etc.) will lead to the activation of a GPCR recptor which leads to the activation of phospholipase C. Activation of phospholipase C leads to breakdown of phosphatidyl 4,5-bisphosphate (PIP)2 into diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3).
2) IP3 binds to IP3 gated channels on the endoplasmic reticulum and leads to in increase in intracellular Ca2+. This Ca2+ and the DAG obtained from phospholipase C are then able to activate protein kinase C (PKC), which leads to the activation of the MAP kinase cascade (RAF-1, MEK, ERK).
3) The MAP kinase cascade then leads to the phosphorylation of phospholipase A2 (Ca2+ binds to the phospholipase A2 as well in addition to the phosphorylation through the MAP kinase cascade, both of which are necessary for activation of phospholipase A2).
4) This phospholipase A2, once activated, can then cut the arachidonic acid from the cell membrane (as told above).
Once the free arachadonic acid is released, a specific cyclooxygenase (COX) is going to help produce the prostaglandins necessary.
What are cyclooxygenases responsible for (with regards to eicosanoids)?
Cyclooxygenases (1 and 2) catalyze the committed step in the “cyclic pathway” that leads to the production of prostaglandins, prostacyclins, and thromboxanes. Essentially, after this step, prostaglandins will be made (point of no return).
How many cyclooxygenases are there, and what order do these need to act in for prostaglandin synthesis?
The are somewhat interchangeable (either can act on the substrates needed to produce the oxygen/ring containing prostaglandin of interest). COX-1 is constitutive (meaning it is always active in production of these prostaglandin), COX-2 is inducible (meaning that if need be, this one can be activated through specific signaling to form a specific prostaglandin).
Prostaglandins are synthesized from ______, mostly from ______.
Prostaglandins are synthesized from essential fatty acids, mostly from arachidonic acid.
Arachidonic acid is attached to specific glycerophospholipids in the cell membrane through an _____ linkage - especially to phosphatidyl inositol that is preset in the cell membrane.
How is arachidonic acid freed from this linkage?
through an ester linkage
In order to free arachidonic acid from this ester linkage phospholipase A2 must be activated to cleave arachidonic acid away from phosphatidyl inositol
Why might it be beneficial that drugs are designed to target cyclooxygenases (1 or 2)? Explain with examples.
The reason that specific drugs are designed to target cyclooxygenases 1 or 2 is because cyclooxygenases are the committed step of cyclic prostaglandin synthesis - meaning that these enzymes are highly regulated when it comes to synthesis of prostaglandins/prostacyclins/thromboxanes. As a result, designing drug which target these enzymes (to either be more or less active) can help with treatment of certain diseases involved in inflammatory responses.
Why is COX-2 tightly regulated?
COX-2 (cyclooxygenase 2) is tightly regulated because it is involved in inflammatory responses.
