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Prolactin Signaling Pathway

Figure1. Prolactin signaling pathway.

Prolactin overview

Prolactin is a hormone with more than 300 independent functions. It is mainly secreted by the anterior pituitary cells and can be synthesized and secreted by other extensive cells in the body. These cells include various immune cells, brain and decidual cells of the uterus, skin cells, etc. Many experimental results have shown that PRL is present in all vertebrates. It forms a gene family with growth hormone (GH) and placental lactogen (PL), which are evolved from the same original gene, and determine the PRL and GH systems. The differences occurred 400 million years ago. As a member of the family of growth hormones and their derivatives, PRL stimulates breast growth, initiates milk synthesis, and maintains lactation. To achieve these functions, PRL must work synergistically with reproduction, metabolism, and some local pathways, and other hormones such as estrogen, progesterone (PROG), glucocorticoid (GCS), and insulin (INS) are also critical. Regulatory factors are involved. In the process of synthesizing milk components in the mammary gland, there is also a synergistic regulation between PRL and estrogen, PROG, GCS, INS and other hormones.

Prolactin family

The protein structure of PRL consists of four alpha helices arranged in a similar manner to GH. Post-translational modifications of mature PRL include glycosylation, phosphorylation or proteolysis. PRL binds to the prolactin receptor (PRLR) on the surface of the target cell membrane and initiates a corresponding intracellular signal transduction process to achieve its biological function. The prolactin receptor and the growth hormone receptor belong to the type I cytokine receptor superfamily. There are two types of protein molecules that can recognize and bind PRL. One type mainly refers to the prolactin receptor which is present on the surface of the cell membrane, membrane-bound PRLR; the other type refers to the soluble prolactin-binding protein present in the blood and milk (PLRbp). Membrane-bound prolactin receptors, depending on the length of the intramembrane region, contain several species; in the case of human prolactin receptors, there are currently at least four types. Two short receptors, SF1a and SF1b. The four membrane-bound prolactin receptors are composed of the extramembranous region (ECD), the transmembrane region (TD), and the intramembranous region (ID). The difference between the four receptors is mainly in the intramembrane region, and the transmembrane region and the extramembranous region are identical. The soluble prolactin-binding protein (PRLbp) has no transmembrane region and intramembrane region and is composed of 1 to 206 amino acid residues in the extracellular region of the conjugated prolactin receptor. The presence of PRLbp may be related to the regulation of blood and milk PRL concentrations, and it has been reported to have an effect of antagonizing the biological effects of PRL.

Prolactin signaling pathway

  1. Prolactin signaling pathway cascade
  2. Prolactin can act as a classic endocrine regulator for various physiological activities of animals by entering the circulatory system or locally through the form of proximal secretory, paracrine and autocrine activities: 1). Prolactin promotes mammary gland development and milk production. Prolactin promotes the growth and differentiation of mammary lobular vesicles. Prolactin works with cortisol and insulin to stimulate the transcription of the milk protein gene, which stimulates milk production or milk production after birth; 2). Prolactin is not only produced and secreted by the pituitary but also synthesized and secreted by the immune cells themselves. Prolactin broadly affects the proliferation and differentiation of various cells within the immune system. In addition, it is closely related to the occurrence and development of many immune-related diseases (such as systemic lupus erythematosus, hyperprolactinemia, and rheumatoid arthritis). Although prolactin has a regulatory effect on immune function, these reactions are not strictly necessary for prolactin; 3). Prolactin can stimulate the secretion of progesterone in the corpus luteum during the estrous cycle of mammals and provide a raw material for the synthesis of progesterone. PRL can also directly act on ovarian granulosa cells, inhibit follicle-induced granulocyte aromatase inactivation, reduce estradiol synthesis, and inhibit ovulation; 4). Prolactin plays an important role in regulating the balance of water and electrolytes. It is a hormone that adapts to living water. PRL can significantly reduce the loss of Na+, reduce the increase of water flow or water permeability in the sputum, and increase the extracellular accumulation of mammals. PRL shows the effect of reducing Na+ and K+ excretion. PRL reduces sweat Na+ and Cl- increases the absorption of water and salt in various parts of the intestine. PRL can cause a decrease in fluid in the amniotic membrane.

  3. Pathway regulation
  4. In addition to the above main functions, PRL also has many special functions, such as PRL directly acting on sheep glands, regulating testosterone secretion, and participating in testosterone synthesis. PRL can induce the growth of larvae and regulate the nesting behavior of birds. In mammals, the transcription factor pit-1/G HF-1 promotes the expression of the PRL gene. Thyroid stimulating hormone (TRH), epidermal growth factor (EGF), and vasoactive intestinal peptide (VIP) also promote PRL expression. Among them, the regulation of VIP is through the cAMP pathway, and it is important to increase the level of cellular cAMP to promote the expression of the PRL gene. Prolactin is extremely sensitive to estrogen. When estrogen binds to endogenous cellular receptors, it synergizes with pituitary-specific factor pit-1 to stimulate the synthesis and secretion of prolactin. Prolactin is mainly synthesized and secreted by PRL cells in the anterior pituitary. There are also many tissue cells in the pituitary, such as uterine decidual cells and decidual stromal cells secreting PRL, but the two secretory and storage methods are different. The PRL synthesized by the pituitary PRL cells forms a large aggregate when passing through the Golgi complex, and is stored in the form of secretory granules in combination with the storage protein. The PRL secreted by the pituitary tissue does not form secretory granules. There are two main ways to secrete PRL: direct secretion and secretion of secretory granules. The basal secretion is mainly the direct secretion of secretory granules and the release of part of the secretory granules, and the secretion is mainly the release of secretory granules. The level of PRL in the human body is constantly changing. At the 5th week of pregnancy, the anterior pituitary of the fetus can secrete PRL. The secretion of fetal PRL increases progressively with the progress of pregnancy, reaching 4.55 to 9. 10 nmol/L. The level of PRL in neonates after birth drops sharply and falls to a low level 3 month after birth. The PRL of amniotic fluid during pregnancy is derived from the secretion of decidual cells. By 10 weeks of gestation, the level of amniotic fluid PRL is parallel to the level in maternal plasma. After 20 weeks of gestation, the level of PRL in amniotic fluid increases significantly, higher than that in fetal blood and maternal blood. The PRL level is then lowered until delivery. Decidual membrane PRL secretion is not affected by dopamine, which plays a very important role in the regulation of fluid and electrolytes in amniotic fluid. During pregnancy, due to the action of estrogen, the number of pituitary PRL cells is increased, the volume is increased, and the secretion of PRL is also increased. The level of PRL during pregnancy increases from 8 weeks to gestation, and the level of PRL in pregnant women is above 9.1 nmol/L. Although the PRL level during pregnancy is high, there is no lactation. Neuroendocrine regulation of the hypothalamus: the secretion of pituitary PRL is mainly regulated by the hypothalamus. The hypothalamus can secrete both PRL inhibitors and PRL releasing factors. However, the hypothalamus mainly inhibits the secretion of PRL. Prolactin releases inhibitors. In the early 1960s, Mites et al. demonstrated that the hypothalamus contains substances that inhibit PRL secretion and is called prolactin release inhibitor (PIF). Including 1 dopamine (DA): DA is currently considered to be the most important and potent PIF secreted by the hypothalamus, but not the only PIF. It has been shown that the hypothalamus has a higher concentration of DA, which can reach the anterior pituitary through the pituitary portal system and bind to the DA receptor on the pituitary PRL surface. The mechanism by which DA inhibits PRL release is mainly that DA binds to the receptor and causes a decrease in intracellular cAMP, thereby inhibiting the release of PRL; in addition, DA inhibits the influx of extracellular calcium ions. Peripheral Hormone Regulation: Estrogen is a peripheral hormone that primarily promotes the synthesis and release of PRL. The possible mechanism of action is: 1). Estrogen can directly stimulate PRL gene expression. When estrogen binds to PRL cell receptors, it induces an increase in PRL gene mRNA expression; 2). Estrogen stimulates proliferation of pituitary PRL cells. Estrogen self-feedback regulation: PRL regulates the secretion of the estrogen through the hypothalamus. When the blood and pituitary local PRL levels are elevated, it can promote the release of DA from the hypothalamus and inhibit PRL secretion, resulting in negative feedback.

  5. Relationship with diseases
  6. Hyperprolactinemia

    Hyperprolactinemia is a common clinical endocrine disease. The serum prolactin level is about 1.14 nmol/L in patients. It has also been shown that high prolactin can be improved to some extent by inhibiting the release of prolactin.

    Pituitary breast tumor

    The study found that in patients with pituitary breast tumors, the content of prolactin is abnormally high, and the individual differences are extremely great. The role of prolactin in the occurrence and development of pituitary breast tumors remains to be further studied. There is ample evidence that inhibition of prolactin release may be a potential therapeutic target for breast tumors.

References:

  1. Bernard V, Young J, Chanson P, et al. New insights in prolactin: pathological implications. Nature Reviews Endocrinology. 2015, 11(5):265-275.
  2. Brown R S E, Herbison A E, Grattan D R. Effects of Prolactin and Lactation on A15 Dopamine Neurones in the Rostral Preoptic Area of Female Mice. Journal of Neuroendocrinology. 2015, 27(9):708-717.
  3. Lychkovq A E, Puzikov A M. Prolactin and serotonin. Vestnik Rossiĭskoĭ Akademii Meditsinskikh Nauk. 2014(1-2):38-45.
  4. Muck-Seler D, Pivac N, Mustapic M, et al. Platelet serotonin and plasma prolactin and cortisol in healthy, depressed and schizophrenic women. Psychiatry Res. 2004, 127(3):217-226.

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