Questions And Answer | Back Directory | [Discovery]
The classical PRL (PRL1) was first discovered in rabbits and pigeons as the milk-secreting factor around
1930, and confirmed in humans in 1971. To date, PRL1
has been reported in all major gnathostome classes while
PRL1s in amniotes and fish are encoded by distinct genes
(PRL1A and PRL1B, respectively). It is most likely that the
fish-type PRL1B gene was duplicated in an early amphibian to generate the amniote-type PRL1A gene. The
amphibians are the only extant vertebrates that maintain
both the fish- and amniote-type PRL1 genes; the PRL1B
gene was lost in the amniotes. Some teleosts have an
additional copy of the PRL1 gene, suggesting that the
PRL1B gene went through a further duplication event in these species, but the time point and the possible
involvement of the proposed teleost-specific tetraploidization are unclear. PRL2 was identified in 2009 in nonmammalian vertebrates by bioinformatic analysis, and
the classical PRL was subsequently renamed PRL1. Only
a few features of PRL2 are known, and some of the following sections lack a description on PRL2. | [Structure]
PRL1 consists of about 200 aa residues in most species. In tetrapods, sturgeon,
and lungfish, PRL1 has three disulfide bonds, the first
forming a small loop near the N-terminus, the second linking distant parts of the polypeptide chain, and the third
forming a loop close to the C-terminus. In cartilaginous
fish and Halecomorphi (teleosts and the Amiiformes),
PRL1 lacks the first disulfide bond at the N-terminus.
Molecular heterogeneity in regard to glycosylation, phosphorylation, and sulfation has been described. The nonglycosylated form of PRL1 is the dominant form of
PRL1 that is secreted from the pituitary. PRL2 is similar
to PRL1 in its length and structure. It also contains three
disulfide bonds, with the only exception being the shark
PRL2, which lacks the one in the N-terminal region3. The evolution of PRL1 in mammals shows a similar
pattern to that for GH, with a fairly slow basal evolutionary rate but accelerated evolution in lineages leading to
humans, ruminants, elephants and rodents. In fish,
including teleosts and sturgeon, PRL1 shows a great deal
of structural variation, as seen for GH. The amino acid
sequence identity between PRL1 and PRL2 is approximately 30%.
| [Gene, mRNA, and precursor]
The human PRL1 gene, PRL, location 6p22.3, consists
of five exons. Alternative splicing gives rise
to variant mRNAs and therefore proteins. The chicken
and zebrafish PRL1 genes are located on chromosome 2
and 3, respectively. The PRL2 genes of these species are
also comprised of five exons, located on chromosome 1
(chicken) and 4 (zebrafish). PRL1 mRNA is detected most abundantly in the acidophilic lactotropes in the anterior pituitary. Transcripts are
also found in the decidua, myometrium, breast, lymphocytes, leukocytes, intestine, and prostate. On the other
hand, the gene expression of PRL2 is restricted to the
extrapituitary tissues. | [Synthesis and release]
Pit-1 is a transcription factor that binds to several sites
in the promoter of the PRL1 gene to allow for the synthesis of PRL1 in the anterior pituitary. Most extrapituitary
production of PRL1 is controlled by a superdistal promoter. Neurosecretory dopamine neurons inhibit
PRL1 secretion via D2 receptors. Estrogens are also key
regulators of PRL1 production by enhancing PRL1 cell
growth as well as by stimulating PRL1 production
directly. Thyrotropin-releasing hormone and PRLreleasing peptide-2 have a stimulatory effect on PRL1
release. Vasoactive intestinal peptide regulates prolactin
secretion in humans. Unlike PRL1 expressed predominantly in the pituitary, the 50
-flanking region of the
chicken PRL2 gene exhibits a strong promoter activity
in nonpituitary-derived cells. | [Receptors]
The PRL receptor (PRLR) belongs to the class
I cytokine receptor family, and consists of an extracellular
region that binds PRL, a transmembrane region, and a
cytoplasmic region. There is a variation of
PRLR isoforms among different tissues due to expression
from multiple promoters and alternative splicing. When PRL binds to its receptor, it causes dimerization
of the receptor. This results in the activation of JAK2, a
tyrosine kinase that initiates the JAK/STAT pathway.
Activation of the PRL receptor also results in the activation of MAPK and Src kinase. | [Antagonists]
Various candidates have been generated by different
laboratories, but none has yet entered clinical trials. One of them, namely Δ1–9-G129R-hPRL, appears to be
promising, as it is the only one displaying both PRLR
specificity and pure antagonism. | [Biological functions]
PRLRs are present in various tissues, including the
mammary glands, ovary, pituitary, heart, lung, thymus,
spleen, liver, pancreas, kidney, adrenal gland, uterus,
skeletal muscle, skin, gill, and central nervous system. Although PRL1 is often associated with milk production,it has a wide range of physiological roles in humans and
other vertebrates. Control of water and salt balance is an
important function, especially in teleost fish. PRL1 controls the levels of sex steroids as a gonadotropic hormone.
PRL1 has important cell cycle-related functions, acting as
growth, differentiating, and antiapoptotic factors, especially in hematopoiesis, angiogenesis, and the immune
system. Tumors in peripheral tissues synthesize PRL1
to stimulate its own growth via paracrine/autocrine
pathways. PRL1 also stimulates the proliferation of oligodendrocyte precursor cells that differentiate into oligodendrocytes responsible for the formation of myelin
coating in the central nervous system, and may control
behavior. In zebrafish, PRL2 can activate only one of
two PRLR isoforms. Although the physiological function of PRL2 is not clear, it may play a role in the local regulation of extrapituitary tissues via PRLRs. | [Clinical implications]
Hyperprolactinemia or excess serum PRL1 is associated with hypoestrogenism, anovulatory infertility, oligomenorrhoea, amenorrhea, unexpected lactation, and
loss of libido in women, and erectile dysfunction and loss
of libido in men. Hypoprolactinemia is associated with
ovarian dysfunction in women, and metabolic syndrome,
anxiety, arteriogenic erectile dysfunction, premature ejaculation, oligozoospermia, asthenospermia, hypofunction
of seminal vesicles, and hypoandrogenism in men. In
hypoprolactinemic men, normal sperm characteristics
were restored when PRL1 levels were brought up to normal values. |
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