Lipid Signaling

Question 1

Most histamine is generated in granules in ___ or ____

Answer 1

Mast cells

Basophils

Question 2

What triggers degranulation?

Answer 2

Allergic reactions

Anaphylaxis

Celllar destruction

Question 3

Signaling molecules that are stored (ex: histamine) are _____.

A) Hydrophobic

B) Hydrophilic

C) Liphophilic

D) Lipophobic

Answer 3

D

Question 4

Are lipid signaling molecules stored in the body?

Answer 4

No - most are generated on - demand from phospholipid precursors

Question 5

Answer 5

Question 6

Describe how arachidonic acid is liberated from the cell membrane.

Answer 6

Trauma –> release of histamine –> histamine binds to H1 receptor (G_aq receptor) –> a_q subunit stimulates PLC –> PLC cleaves PIP₂ into DAG and IP₃ –> IP₃ stimulates Ca²⁺ release which stimulates PLA₂ which increases arachidonic acid production –> DAG is acted upon by DAG lipase which produces AA and mAA

Question 7

What is a eicosanoid?

Answer 7

Signaling molecule made of 20 carbon fatty acids

Question 8

How does arachidonic acid relate to eicosanoids?

Answer 8

AA is the main precursor for eicosanoids

Question 9

How is PLA₂ stimulated?

Answer 9

Phosphorylation and Ca2+ release

Question 10

What is a leukotriene?

Answer 10

Structure with conjucated triene system of double bonds produced by white blood cells

Question 11

How do leukotrienes relate to Arachidonic acid?

Answer 11

Leukotrienes synthesized from AA by lipoxygenease pathways.

Question 12

Lipoxygenases synthesize leukotrienes from arachidonic acid. Where are these enzymes primarily located?

Answer 12

Platelets, lungs, mast cells, WBC

Question 13

1. 5-lipoxygenase is the main enzyme that produces leukotrienes. What is its substrate and what is the product?
2. What is the product converted to?

Answer 13

1. Substrate: 5-HpETE Product: LTA₄
2. LTA₄ –> LTB₄ or cysteinyl-leukotrienes

Question 14

Where is LTB₄ metabolized?

Answer 14

By membrane bound cytochrome P450 in neutrophils

Question 15

Leukotriene receptors are termed ___ if their ligand is LTB4 and _____ if their ligand is cysteinyl-leukotrienes.

Answer 15

BLT

CysLT

Question 16

Stimulation of BLT receptors results in what in terms of an immune response? (4)

Answer 16

Adherence

Chemotaxis

Activation of neutrophils + monocytes

Stimulates proliferation and cytokine production

Question 17

• Stimulated of CysLT receptors causes what in terms of a physiologic response? (2)

Answer 17

• Bronchoconstriction
• Vasodilation everywhere except the heart and lungs, in which it causes vasoconstriction

Question 18

Stimulation of BLT receptors is an important mediator of ______.

Stimulation of CysLT receptors is an important mediator of _____.

Answer 18

Inflammation

Asthma

Question 19

LTB4 is a potent ______ agent for neutrophils and macrophages.

Answer 19

Chemotactic

Question 20

Arachidonic acid can be acted upon by cyclooxygenases as well as lipoxygenases.

• COX 1 is present in ___ cells and is ____ expressed and produces ____
• COX 2 is _____ normally present, but is ____ by inflammatory stimuli

Answer 20

• most, constitutively, prostanoids
• not, strongly induced

Question 21

Position 523 in the COX 1 and COX 2 primary amino acid sequence is important for its catalytic function.

• What AA is present in COX 1 vs. COX 2 at this position?
• What effect does this single AA change have on the COX 1 vs. COX 2 function?

Answer 21

• COX 1 = Ile COX 2 = Val
• Val is smaller than Ile and allows COX 2 to access hydrophobic side pocket in enzyme which is sterically hindered in COX 1

Question 22

What are the 5 bioreactive end products of COX 1 and COX 2 acting on arachidonic acid?

Answer 22

PGE₂

PGI₂

PGD₂

PGF_2alpha

TXA₂

Question 23

Before arachidonic acid is converted to bioreactive prostaglandins, it is converted to 2 unstable and highly reactive prostaglandins ____ and ____.

Answer 23

PGG₂ and PGH₂ (ultimately what can become bioreactive prostaglandins)

Question 24

TXA₂ has what effect on the vascular system and respiratory system?

Answer 24

• Vasoconstriction and prothrombotic agents
• Bronchoconstriction

Question 25

PGF₂ has what effect on the uterus?

Answer 25

Constricts myometrial smooth muscle to help shed endometrial lining

Question 26

What effect does PGE2 have on the GI system and the hypothalamus?

Answer 26

* Increased gastric acid secretion, mucus secretion, and bicarbonate secretion --\> protects stomach * Increased thermoregulatory setpoint

Question 27

What effect does PGD₂ have on the uterus?

Answer 27

Relaxes the smooth muscle of the uterus

Question 28

What effect does PGI₂ have on the cardiovascular system? What is a synonym for this prostaglandin?

Answer 28

Vasodilation and antithrombosis Prostacyclin

Question 29

Increased PGI₂ results in increased \_\_\_.

Answer 29

Bradykinin --\> vasodilation, increased pain sensitization

Question 30

Describe the half life of prostaglandins.

Answer 30

They are synthesized from prostanoic acid and rapidly taken up and inactivated.

Question 31

THC is a lipophilic endocannabinoid. It binds to 2 receptors, CB1 and CB2. CB1 is found in the ____ and CB2 is found in the \_\_\_\_.

Answer 31

CNS Peripheral tissues

Question 32

How do endocannabinoids relate to arachidonic acid?

Answer 32

Endocannabinoids --\> metabolized to anandamide --\> metabolized to arachidonic acid--\> acted upon by COX and LOX

Question 33

What effect do endocannabinoids have on leukocytes and inflammation?

Answer 33

They act on leukocytes to oppose the action of proinflammatory and chemotactic stimuli (oppose LTB4 action) supplying stop signals to dampen immune response

Question 34

On the surface, it seems contradictory that endocannabinoids are metabolized to arachidonic acid, which is further metabolized to prostaglandins and leukotrienes that mediate inflammation and pain sensitization, yet the physiological response to endocannabinoids is pain relief. Explain how this is possible.

Answer 34

The binding of endocannabinoids to CB1 and CB2 receptors in CNS and PNS results in anti-inflammation and chemotactic stimuli which far outweighs the proinflammatory and pain sensitization caused by prostaglandins and leukotrienes.

Question 35

Describe how acetaminophen exerts analgesic effects.

Answer 35

It inhibits the reuptake of endogenous canabinoids by neurons thus increasing endocannabinoid signaling effects. Because endogenous cannabinoids last longer in the neurons, the CB1 receptors are able to exert greater effects. Endocanabinoid binding to CB1 causes hyperpolarization of pain sensing neurons resulting in analgesia.

Question 36

What are the 3 eicosanoids that were discussed in this block?

Answer 36

Leukotrienes Prostaglandins Thromboxanes