prostaglandins receptor

1. PROSTAGLANDINS
COOH
O
HO
OH
PGE2
Bhagya Siripalli,
Department of Pharmacology,
SVIPS.

2. Prostaglandins and related compounds are collectively known as
eicosanoids.
Most are produced from arachidonic acid, a 20-carbon
polyunsaturated fatty acid (5,8,11,14-eicosatetraenoic acid).
The eicosanoids are considered "local hormones."
They have specific effects on target cells close to their site of
formation.
They are rapidly degraded, so they are not transported to distal
sites within the body.
 But in addition to participating in intercellular signaling, there
is evidence for involvement of eicosanoids in intracellular
signal cascades.
INTRODUCTION

3. DISCOVERY OF PROSTAGLANDINS
• It was discovered by Ulf Von Euler (1930)
• He extracted from human semen.
• It is secreted from prostate gland.
• Structure of prostaglandins - proposed by
Bergstrom (1950).

4. Examples of eicosanoids:
prostaglandins, prostacyclins,
thromboxanes, leukotrienes,
epoxyeicosatrienoic acids.
They have roles in:
inflammation
fever
regulation of blood pressure
blood clotting
immune system modulation
control of reproductive processes &
tissue growth
regulation of sleep/wake cycle.

5. COOH
Arachidonic acid
PGE2
(prostagland
in E2 ) is an
example of a
prostaglandin,
produced from
Arachidonic acid.
COOH
O
HO
OH
PGE2

6. Prostaglandin receptors:
Prostaglandins & related compounds are transported
out of the cells that synthesize them.
Most affect other cells by interacting with plasma
membrane G-protein coupled receptors.
Depending on the cell type, the activated G-
protein may stimulate or inhibit formation of
cAMP, or may activate a phosphatidylinositol signal
pathway leading to intracellular Ca++release.

7. • Prostaglandin receptors are specified by the same letter code.
E.g., receptors for E-class prostaglandins are EP. Thromboxane
receptors are designated TP.
•Multiple receptors for a prostaglandin are specified by subscripts
(E.g., EP1, EP2, EP3, etc.)
•Different receptors for a particular prostaglandin may activate
different signal cascades.
•Effects of a particular prostaglandin may vary in different tissues,
depending on which receptors are expressed.E.g., in different cells
PGE2 may activate either stimulatory or inhibitory or G-proteins,
leading to either increase or decrease in cAMP formation.

8. Prostaglandin H2 Synthase catalyzes the committed step in the “cyclic
pathway” that leads to production of prostaglandins, prostacyclins, &
thromboxanes.
Different cell types convert PGH2 to different compounds.
leukotrienes
phospholipids arachidonate diacylglycerol
prostaglandin H2
prostacyclins thromboxanes
other prostaglandins
PGH2 Synthase
Prostacyclin
Synthase
Thromboxane
Synthase
Linear pathway Lipoxyganase
Cyclic pathway
Two major
pathways of
eicosanoid
metabolism.
Cyclic
pathway:

9. PGH2Synthase is a heme-
containing
dioxygenase, bound to ER
membranes.
(A dioxygenase
incorporates O into a
substrate). PGH2
Synthase exhibits 2
activities:
cyclooxygenase &
peroxidase.
COOH
COOH
O
O
OH
COOH
O
O
2 O2
2 e
arachidonic acid
PGG2
PGH2
Cyclooxygenase
OOH
Peroxidase

10. They inhibit formation of prostaglandins
involved in fever, pain, & inflammation.
They inhibit blood clotting by
blocking thromboxane formation in
blood platelets.
Ibuprofen and related compounds block the
hydrophobic channel by which arachidonate
enters the cyclooxygenase active site.
Non-steroidal anti-inflammatory drugs
(NSAIDs), such as aspirin and derivatives of
ibuprofen, inhibit cyclooxygenase activity of
PGH2 Synthase.
CH
CH2
CH
CH3H3C
H3C COOH
Ibuprofen

11. Aspirin acetylates a serine hydroxyl group near the active site, preventing
arachidonate binding.
The inhibition by aspirin is irreversible. However, in most body cells re-
synthesis of PGH2 Synthase would restore cyclooxygenase activity.
Aspirin
+
+
PGH2 Synthase (active)
COOH O
O C CH3
2Enz-Ser CH OH
COOH
OH
Salicylic acid Acetylated PGH2 Synthase (inactive)
O
Enz-Ser CH2 O C CH3

12. Thromboxane A2stimulates blood platelet aggregation,
essential to the role of platelets in blood clotting.
Many people take a daily aspirin for its anti- clotting
effect, attributed to inhibition of thromboxane
formation in blood platelets.
This effect of aspirin is long-lived because platelets lack a
nucleus and do not make new enzyme.

13. Type Receptor Receptor type Function
PGI2 IP Gs
•vasodilation
•inhibit platelet aggregation
•bronchodilation
PGD2
PTGDR (DP1) and CRTH2
(DP2)
GPCR
•produced by mast cells; recruits Th2 cells, eosinophils,
and basophils
•In mammalian organs, large amounts of PGD2 are found
only in the brain and in mast cells
•Critical to development of allergic diseases such as
asthma
PGE2
EP1 Gq
•bronchoconstriction
•GI tract smooth muscle contraction
EP2 Gs
•bronchodilation
•GI tract smooth muscle relaxation
•vasodilation
EP3 Gi
•↓ gastric acid secretion
•↑ gastric mucus secretion
•uterus contraction (when pregnant)
•GI tract smooth muscle contraction
•lipolysis inhibition
•↑ autonomic neurotransmitters
•↑ platelet response to their agonists and ↑
atherothrombosis in vivo
Unspecified
•hyperalgesia
•pyrogenic
PGF2α FP Gq
•uterus contraction
•bronchoconstriction
TYPES

14. FUNCTIONS
 There are currently ten known prostaglandin receptors on various cell
types. Prostaglandins ligate a sub-family of cell surface seven-
transmembrane receptors, G-protein-coupled receptors.
 These receptors are termed DP1-2, EP1-4, FP, IP1-2, and TP, corresponding
to the receptor that ligates the corresponding prostaglandin (e.g., DP1-2
receptors bind to PGD2).
 The diversity of receptors means that prostaglandins act on an array of
cells and have a wide variety of effects such as:
 create eicosanoids hormones
 acts on thermoregulatory center of hypothalamus to produce fever
 increases mating behaviors in goldfish.
 Prostaglandins are released during menstruation, due to the destruction of
the endometrial cells, and the resultant release of their contents.
 Release of prostaglandins and other inflammatory mediators in
the uterus cause the uterus to contract. These substances are thought to
be a major factor in primary dysmenorrhea. Others say,
that prostaglandins and leukotrienes are released during menstruation,
due to the build up of omega-6 fatty acids

15. CLINICAL USES
Synthetic prostaglandins are used:
 To induce childbirth (parturition) or abortion (PGE2 or PGF2, with or
without mifepristone, a progesterone antagonist)
 To prevent closure of ductus arteriosus in newborns with
particular cyanotic heart defects (PGE1)
 As a vasodilator in severe Raynaud's phenomenon or ischemia of a
limb
 In pulmonary hypertension
 In treatment of glaucoma (as in bimatoprost ophthalmic solution, a
synthetic prostamide analog with ocular hypotensive activity) (PGF2α)
 To treat erectile dysfunction or in penile rehabilitation following
surgery (PGE1 as alprostadil.
 To measure erect penis size in a clinical environment.
 To treat egg binding in small birds