Trends in Biosciences 8(15), Print : ISSN 0974-8, 3827-3830, 2015

Biophysiology of the Prostaglandins and its Receptors

SANJAY C. PARMAR1*, B. B. RAJGOR2, K. V. BUHECHA3 AND C. P. PARMAR3
1&3

College of Veterinary Science & A.H., AAU, Anand, Gujarat, India

Maahi Dairy, Junagadh, Gujarat, India
*
email: dr.sanjayparmar@yahoo.in
2

ABSTRACT
Prostaglandins are derivatives of prostanoic
acid and they are 20-carbon fatty acids with a
cyclopentane ring at C-8 to C-12. They are
produced by all nucleated cells except lymphocytes.
They are autocrine and paracrine lipid mediators
that act upon platelets, endothelium, uterine and mast
cells. Prostaglandins are potent but have a short
half-life before being inactivated and excreted.
Therefore, they send only paracrine (locally active)
or autocrine (acting on the same cell from which it is
synthesized) signals. Although they are technically
hormones, they are rarely classified as such. The
prostaglandins, together with the thromboxanes and
prostacyclins, form the prostanoid class of fatty acid
derivatives.
Key words

Corpus Luteum, Luteolysis, PGF2,

Prostaglandin, Prostaglandin Receptor

A prostaglandin is any member of a group of

lipid compounds that are derived enzymatically
from fatty acids and have important functions in
the animal body. Every prostaglandin contains 20
carbon atoms, including a 5-carbon ring. They are
mediators and have a variety of strong
physiological effects, such as regulating the
contraction and relaxation of smooth muscle tissue
(Nelson, 2005). Although they are technically
hormones, they are rarely classified as such. The
prostaglandins, together with the thromboxanes and
prostacyclins, form the prostanoid class of fatty
acid derivatives. The prostanoid is a subclass of
eicosanoid.

Biosynthesis of Eicosanoids
Prostaglandins are found in most tissues and
organs. They are produced by all nucleated cells

except lymphocytes. They are autocrine and

paracrine lipid mediators that act upon platelets,
endothelium, uterine and mast cells. They are
synthesized in the cell from the essential fatty acids
(Komoto et al., 2004). An intermediate is created
from phospholipase-A2, then brought out of one
of either the cyclooxygenase pathway or the
lipoxygenase pathway to form either
prostaglandin and thromboxane or leukotriene
respectively. The cyclooxygenase pathway
produces thromboxane, prostacyclin and
prostaglandin D, E and F.

Release of Prostaglandins from the Cell

Prostaglandins were originally believed to
leave the cells via passive diffusion because of their
high lipophilicity. The discovery of the prostaglandin
transporter (PGT, SLCO2A1), which mediates the
cellular uptake of prostaglandin, demonstrated that
diffusion cannot explain the penetration of
prostaglandin through the cellular membrane. The
release of prostaglandin has now also been shown
to be mediated by a specific transporter, namely
the multidrug resistance protein 4 (MRP4, ABCC4),
a member of the ATP-binding cassette transporter
superfamily. Whether MRP4 is the only transporter
releasing prostaglandins from the cells is still
unclear. Prostaglandins are potent but have a short
half-life before being inactivated and excreted.
Therefore, they send only paracrine (locally active)
or autocrine (acting on the same cell from which it
is synthesized) signals.

Types of Prostaglandins
The following is a comparison of different
types of prostaglandin, prostaglandin I2 (PGI2),
prostaglandin E2 (PGE2) and prostaglandin F2
(PGF2).

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Trends in Biosciences 8 (15), 2015

Type

Receptor

PGI2

IP

Vasodilatation.
Inhibit platelet aggregation.
Bronchodilatation.

EP1

Bronchodilatation.
GI tract Smooth muscle contraction

EP2

GI tract Smooth muscle contraction

Vasodilatation.

EP3

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

FP

Luteolysis
Uterine contraction
Bronchoconstriction

PGE2

PGF2

Function

Prostaglandins
Prostaglandins are derivatives of prostanoic
acid. In that they are 20-carbon fatty acids with a
cyclopentane ring at C-8 to C-12. All naturally
occurring prostaglandins have a hydroxyl group at
C-15 and a 13, 14 trans double bond. PGF2 also
has a 5, 6 cis double bond and a hydroxyl functions
at carbons 9 and 11. The subscript 2 in PGF2
refers to two double bonds, i.e., the degree of
unsaturation while denotes the configuration of
the C-9 hydroxyl group only. PGE2 differs from
PGF2 in having a keto-function rather than ahydroxyl group at C-9.

Prostaglandin Receptors
Exogenous PGF2 causes regression of the
bovine CL only between Day 5 and Day 16 after
estrus (Hafs, 1974). This lack of PGF 2
responsiveness could be due to a deficiency in
number or affinity of PGF2 receptors in the early
CL. A variety of other tissues bound small amounts
of 3H-PGF2, but high amounts of specific binding
and high-affinity receptors were found only in CL
and adrenal medulla (Wiltbank et al., 1995). The
affinity of PGF2 receptors was similar in the
adrenal medulla and CL; however, the concentration
of receptors was about four times greater in the
active CL. In sheep and pigs the high-affinity
receptors for PGF2 appear to be specifically located
on the large luteal cells (Gadsby et al., 1990). Large
luteal cells primarily arise from granulosa cells in

the early bovine CL. The lack of PGF2 a receptors

on granulosa cells suggests that during the
luteinization process (prior to 2 days after ovulation),
the cells that differentiate into the large luteal cells
begin to express the gene for the PGF2 receptor.
The induced luteolysis by PGF2 indicate that
it may alter primarily membrane-bound enzyme
activity through an unknown intracellular
mechanism (Kim and Yeoun, 1983). Effects of
Prostaglandin on Corpus Luteum: 1) changes in
the cytoplasmic granule population may be
correlated with luteal progesterone storage and
release, 2) degranulation is specific for luteolytic
prostaglandins, 3) LLC are more sensitive than SLC
to the effects of luteolytic prostaglandins and PGE1,
and 4) changes in lipid inclusions may be secondary
effects of luteolytic prostaglandins (Heath et al.,
1983). Administration of PGF2 to cattle in midcycle
depressed luteal progesterone at 15 mm and the
granule area in LLC within 30 mm. Degranulation
was taking place at 15 mm post-PGF2 treatment
via massive exocytosis and was observed only
following treatment with the luteolytic
prostaglandins. These results together suggest that
the early degranulation effect of PGF2 is at least
indirectly associated with progesterone secretion.
The latter association might explain the initial rise
in plasma progesterone in the first 30 mm following
PGF 2 treatment. Other investigators have
suggested that similar granules in the corpus luteum
contain oxytocin (Flint and Sheldrick, 1982). The

PARMAR et al., Biophysiology of the Prostaglandins and its Receptors

suggestion that the granules contain oxytocin is

intriguing in view of the relationship between
oxytocin administration and release of PGF2 by
the bovine uterus (Milvae and Hansel, 1980).
Results of the various study suggest that
degranulation is a rapid event specific for the
luteolytic prostaglandins. Therefore, it may be
hypothesized that PGF2 initiates exocytosis of
oxytocin which in turn may cause secretion of
more PGF2 by the uterus.

Mechanism Regulating Prostaglandins

Secretion
The mechanism that regulates luteolytic PGF2
secretion as stimulated by oxytocin is thought to
involve induction of the inositol (1, 4, 5)trisphosphatediacylglycerol second messenger
system, which mobilizes intracellular calcium and
activates protein kinase C. Oxytocin (OT) from
both the neurohypophysis and the CL is responsible
for the pulsatile pattern of the secretion of PGF2
from the endometrium, which is critical for effective
CL regression. Although endometrial responsiveness
to OT increases markedly during late diestrus in
cows, the initial increase in endometrial sensitivity
to OT apparently occurs between day 13 and 16
post estrus as a result of the increasing
concentrations of endometrial OT receptors
(Mirando et al., 1993). Once concentrations of the
OT receptors have increased during late, the ability
of OT to stimulate synthesis of uterine PGF2 in
ruminants may be mediated through a rapid increase
in phospholipase (PL) C activity. During the time
that the conceptus acts to rescue the CL from
luteolysis during pregnancy in cows, PGF 2
secretion is reduced. This reduction in PGF 2
secretion during early pregnancy is partially due to
reduced endometrial sensitivity to OT and involves
a reduction in the OT receptor population
(Parkinson et al., 1990) and inhibition of the ability
of OT to stimulate PLC activity (Mirando et al.,
1993). Activated PL C hydrolyzes phosphoinositides
(PI) , presumably leading to the formation of
diacylglycerol (DAG) and inositol (1,4,5)trisphosphate (IP3). Synthesis of PGF2 in the
endometrium is stimulated by DAG, which may act
as a second messenger to activate protein kinase C
(PKC) or may, by serving as a substrate for
monoacylglycerol and diacylglycerol lipases, yield
arachidonic acid. Proteins phosphorylated by PKC
(e.g. PLA2) may be responsible for the mobilization

3829

of arachidonic acid from intracellular pools to serve

as a substrate for PGF2 synthesis. The action of
IP3 as a second messenger is to release calcium
pools within the cell that are sensitive to IP3.
Increases in intracellular calcium may alter
enzymatic activity, especially through binding
proteins such as calmodulin (Cheung, 1980), and
thereby promote PGF2 synthesis.

Metabolism of Prostaglandins
Maximum tritium concentration in plasma
was observed in the first sample taken after
subcutameous injection of fenprostalene. In
ruminants, 65%99% of PGs are metabolized in
the pulmonary vascular bed after a single passage
(McCracken et al., 1999). The first step in the
catabolism of the naturally-occurring PGF2 is
oxidation of the 15-hydroxyl group to a 15-keto
moiety (Hansen, 1976). This is followed by
reduction of the double bond yielding 15-keto-13,
14-dihydro- PGF2 (Kindahl, 1980). A second route
of metabolic degradation of PGF2 is -oxidation
of the -side chain giving 1,2-dinor and 1,2,3,4tetranor acid metabolites.
Tomlinson et al., 1985 stated that urine was
the major route of elimination of fenprostalene
(Synthetic prostaglandin). Recovery of tritium in
urine accounted for 55% of the total dose with
recovery in feces accounting for an additional 43%.
Milk was a very minor route of elimination of
fenprostalene with only 0.46% of the injected dose
recovered over a 7 day sampling (Tomlinson et al.,
1985). While Manns, 1975 reported that 30 mg of
PGF2 increased the concentration of PGF2 in milk
from an average preinjection concentration of 0.3
to 0.8 ng/ml during the first 3 hr after injection in
lactating cows. Reeves, 1978 reported a maximum
mean cloprostenol concentration in milk of 0.3 ng/
ml at 5 hr after injecting 0.5 mg of cloprostenol.
Excretion in urine and feces was essentially
complete by 48 hr with approximately 96% of the
total dose recovered at that time. Total recovery of
tritium in milk, urine, and feces over the entire 7
day collection period averaged 98.76%.
Concentrations of tritium in tissues after injection
of [3H] fenprostalene were higher in kidney and
liver than in muscle or fat. The larger concentrations
in kidney and liver apparently reflect the involvement
of those organs in the excretion of fenprostalene
(Tomlinson et al., 1985).

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Trends in Biosciences 8 (15), 2015

It could be concluded that the prostagladin

are useful in luteolysis due to its luteolytic effect
causing regression of corpus luteum. Moreover,
the prostaglandins increase the responsiveness of
oxytocin and causes relaxation of cervix and
expulsion of uterine contents during parturition. The
prostaglandin can also favor and enhance body
defense mechanism or phagocytic activity.

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Received on 10-07-2015

Accepted on 16-07-2015