Neurokinin B

Last updated
Neurokinin B
Neurokinin B.png
Identifiers
3D model (JSmol)
ChemSpider
MeSH Neurokinin+B
PubChem CID
  • InChI=1S/C55H79N13O14S2/c1-30(2)21-38(50(77)62-36(47(57)74)17-19-83-5)61-43(69)28-59-55(82)46(31(3)4)68-54(81)40(23-33-15-11-8-12-16-33)65-51(78)39(22-32-13-9-7-10-14-32)64-53(80)42(26-45(72)73)67-52(79)41(24-34-27-58-29-60-34)66-49(76)37(18-20-84-6)63-48(75)35(56)25-44(70)71/h7-16,27,29-31,35-42,46H,17-26,28,56H2,1-6H3,(H2,57,74)(H,58,60)(H,59,82)(H,61,69)(H,62,77)(H,63,75)(H,64,80)(H,65,78)(H,66,76)(H,67,79)(H,68,81)(H,70,71)(H,72,73)/t35-,36-,37-,38-,39-,40-,41-,42-,46-/m0/s1 X mark.svgN
    Key: NHXYSAFTNPANFK-HDMCBQFHSA-N X mark.svgN
  • InChI=1/C55H79N13O14S2/c1-30(2)21-38(50(77)62-36(47(57)74)17-19-83-5)61-43(69)28-59-55(82)46(31(3)4)68-54(81)40(23-33-15-11-8-12-16-33)65-51(78)39(22-32-13-9-7-10-14-32)64-53(80)42(26-45(72)73)67-52(79)41(24-34-27-58-29-60-34)66-49(76)37(18-20-84-6)63-48(75)35(56)25-44(70)71/h7-16,27,29-31,35-42,46H,17-26,28,56H2,1-6H3,(H2,57,74)(H,58,60)(H,59,82)(H,61,69)(H,62,77)(H,63,75)(H,64,80)(H,65,78)(H,66,76)(H,67,79)(H,68,81)(H,70,71)(H,72,73)/t35-,36-,37-,38-,39-,40-,41-,42-,46-/m0/s1
    Key: NHXYSAFTNPANFK-HDMCBQFHBC
  • CC(C)C[C@@H](C(=O)N[C@@H](CCSC)C(=O)N)NC(=O)CNC(=O)[C@H](C(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](Cc3c[nH]cn3)NC(=O)[C@H](CCSC)NC(=O)[C@H](CC(=O)O)N
Properties
C55H79N13O14S2
Molar mass 1210.43
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Neurokinin B (NKB) belongs in the family of tachykinin peptides. Neurokinin B is implicated in a variety of human functions and pathways such as the secretion of gonadotropin-releasing hormone. [1] Additionally, NKB is associated with pregnancy in females and maturation in young adults. Reproductive function is highly dependent on levels of both neurokinin B and also the G-protein coupled receptor ligand kisspeptin. [2] The first NKB studies done attempted to resolve why high levels of the peptide may be implicated in pre-eclampsia during pregnancy. [3] NKB, kisspeptin, and dynorphin together are found in the arcuate nucleus (ARC) known as the KNDy subpopulation. This subpopulation is targeted by many steroid hormones and works to form a network that feeds back to GnRH pulse generator. [4]

Contents

Synthesis

Neurokinin B is found in humans as a ten-peptide chain (decapeptide) attached to a terminal amide group. The peptide formula is H-Asp-Met-His-Asp-Phe-Phe-Val-Gly-Leu-Met-NH2 (DMHDFFVGLM-NH2). [5] Neurokinin b (NKB), is encoded by the TAC3 gene in humans and Tac2 in rodent species. [6] Neurokinin b is expressed along with the peptides kisspeptin and dynorphin A in the neuronal cells of the arcuate nucleus. [6] Five exon segments in the TAC3 gene encode for the NKB precursor known as preprotachykinin B. Preprotachykinin B is then proteolytically cleaved into the pro-peptide proneurokinin B. A second proteolytic cleavage of proneurokinin B produces the final product neurokinin B. [6]

Role in humans

During the ovarian cycle, GnRH secretion along with that of luteinizing hormone (LH) is highly regulated. This regulation occurs by a negative feedback system. Neurokinin B along with its sister peptides of the KNDy subpopulation regulate this feedback. The NK3R receptor group when activated with a synthetic agonist of NKB, senktide, has been shown to stimulate the secretion of luteinizing hormone. [4] In addition, studies have shown that NKB plays a larger role in females than in males. It has been found that in brain of females, the arcuate nucleus contains twice as many connections to NKB neurons than males. [1]

Arcuate nucleus shown as AR HypothalamicNuclei.PNG
Arcuate nucleus shown as AR

Receptors

The main receptor neurokinin B interacts with is the neurokinin 3 receptor (NK3R). [6] The Neurokinin 3 receptor is a part of a larger family of G-protein coupled receptors that binds all tachykinin proteins. While neurokinin B has the ability to bind to other Neurokinin receptors, the highest affinity lies in that of the NK3R receptor group. [6] Much like the neurokinin B peptide, the NK3R receptor that it binds to is encoded within five exons of the TACR3 gene in humans and the Tacr3 gene in mice and other rodents. [6] High concentrations of the NK3R receptor are found in both the central nervous system and the spinal cord. Additional NK3R receptors have also been found in various other places in the body including: uterus, mesenteric vein, gut neurons, and placenta. [6] Neurokinin B has also been found to co-localize certain gonadal steroid hormone receptors. These include the estrogen receptor (ERα), progesterone receptor (PR), and androgen receptor. It has been found that co-localization of the NKB neurons near these receptors is at a much higher concentration than even that of other peptides and chemicals. The kisspeptin, neurokinin B, and dynorphin cell groups are found to be co-localized to more than 95% of all of the aforementioned receptors in the arcuate nucleus. [4]

Role of gonadotropin-releasing hormone

Mutations or defects in the TAC3 or TAC3R gene can lead to steroidal feedback problems in the GnRH pulse generator loop, causing GnRH to be understimulated. Lack of GnRH ultimately leads to hypogonadism. [4] A review of neurokinin B and its sister peptides, kisspeptin and dynorphin, in sheep found that these KNDy cell groups (kisspeptin, neurokinin B, dynorphin), are in direct contact with the GnRH neuronal bodies in both the preoptic area and the mediobasal hypothalamus. Researchers found this to be feature to be conserved among species including humans. [4] Due to the high percentage of co-localization found with neurokinin B cell bodies and receptor groups, it is suggested that Neurokinin b along with kisspeptin and dynorphin play a role in the release of GnRH. [4] These findings are important since GnRH release plays such a pivotal role in regulating hormonal control in the bodies of humans.

Role in pre-eclampsia

Pre-eclampsia is a disorder found in around 5% of pregnant women, usually presenting in the 37th week of gestation, with prognosis ranging from mild to severe. [7] While mild forms of the disease do not significantly impact mother or fetus, more severe cases may lead to blood vessel constriction, increased blood pressure, and reduced blood flow. This in turn can damage various organ systems including the brain, liver, kidneys, and heart. Dangers to the fetus occur when restricted blood flow due to high pressures causes a lack of blood flow to the uterus. This can result in a number of problems for the fetus including poor growth, lack of amniotic fluid, and placental abruption. [7]

H&E stain of placenta during pre-eclampsia Hypertrophic decidual vasculopathy high mag.jpg
H&E stain of placenta during pre-eclampsia

The cause of pre-eclampsia is not known. Research indicates that the tachykinin peptide neurokinin B may play a role, as placental expression of the TAC3 gene, which codes for NKB, was found in high levels in women with pre-eclampsia. [8]

Usually not located in peripheral tissue, high levels of TAC3 gene were found in both maternal plasma and placental blood, including blood from the umbilical cord. TAC3 in this case was able to secrete NKB in order to affect the circulation of the fetus. Additional studies done on rodents introduced to high levels of NKB indicated the vasoregulatory properties of the peptide, such as the vasoconstriction found in cases of pre-eclampsia. [8]

Increased NKB secretions seem to be caused by defective implantation or invasion of the embryo at the trophoblast stage. In most cases of pre-eclampsia, the trophoblast was unable to fully invade into the uterine lining and has been an almost constant feature in documented cases. This leads to increased signaling of NKB factors. In cases of defective implantation, NKB is vital to increase blood flow to the placenta. However, it seems as though depending on which receptor NKB binds, the peptide can cause both constriction and dilation of the blood vessels. The NK1 receptor was studied and found to cause vasodilation while the NK3 receptor was found to cause vasoconstriction. Higher levels of NK3 receptor seem to be found in pregnant woman suffering from pre-eclampsia. NKB usually found in the brain, has been found in the placenta at a concentration of 2.6 times that of the NKB in the brain, [8] possibly leading to the onset of pre-eclampsia in mothers.

Studies in non-human animals

Much like the human TAC3 gene, Tac2 in rodents facilitates the expression of the neurokinin B peptide. [9] Rodent studies have been done and compared to human studies to elucidate the function of NKB. For cases in which human studies are not possible, rodent studies are substituted due to the conserved similarity between TAC3 and Tac2, and NKB with the TAC3R and Tac2r receptor genes.

Studies show that in postmenopausal woman there is an increased expression of tachykinin neurons in the arcuate nucleus. [10]

In order to replicate the condition of the post-menopausal woman, an ovariectomized rat is used. The removal of the ovaries simulates the condition of menopause in rats and allows for comparative studies to be done. It was found that in these ovariectomized rats there was a significant increase in the number of NKB neurons in the arcuate nucleus. [10]

Along with rats, primate studies have been done, investigating the effects of NKB and the other peptides of the KNDy subpopulation. Due to the similarity in brain structure monkeys have been good research candidates. In humans, as previously mentioned, NKB signaling plays a vital role in hormone secretion, especially that of luteinizing hormone before the onset of puberty. It was shown, in monkeys, that activation of NK3R, the NKB receptor, was associated with release of hormones that come before the onset of puberty. This included initial release of GnRH. NKB found mostly in the arcuate nucleus in humans, is found mostly in the monkey hypothalamus. By injecting NKB analogs pulsatile GnRH was secreted, activating the hypothalmic-pituitary axis and therefore releasing LH. Researchers found these results consistent across both monkey and human brains. [11]

Related Research Articles

Substance P Chemical compound

Substance P (SP) is an undecapeptide member of the tachykinin neuropeptide family. It is a neuropeptide, acting as a neurotransmitter and as a neuromodulator. Substance P and its closely related neurokinin A (NKA) are produced from a polyprotein precursor after differential splicing of the preprotachykinin A gene. The deduced amino acid sequence of substance P is as follows:

Supraoptic nucleus ADH secreting nucleus of the hypothalamus.

The supraoptic nucleus (SON) is a nucleus of magnocellular neurosecretory cells in the hypothalamus of the mammalian brain. The nucleus is situated at the base of the brain, adjacent to the optic chiasm. In humans, the SON contains about 3,000 neurons.

Paraventricular nucleus of hypothalamus

The paraventricular nucleus is a nucleus in the hypothalamus. Anatomically, it is adjacent to the third ventricle and many of its neurons project to the posterior pituitary. These projecting neurons secrete oxytocin and a smaller amount of vasopressin, otherwise the nucleus also secretes corticotropin-releasing hormone (CRH) and thyrotropin-releasing hormone (TRH). CRH and TRH are secreted into the hypophyseal portal system and act on different targets neurons in the anterior pituitary. PVN is thought to mediate many diverse functions through these different hormones, including osmoregulation, appetite, and the response of the body to stress.

Gonadotropin-releasing hormone Mammalian protein found in Homo sapiens

Gonadotropin-releasing hormone (GnRH) is a releasing hormone responsible for the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. GnRH is a tropic peptide hormone synthesized and released from GnRH neurons within the hypothalamus. The peptide belongs to gonadotropin-releasing hormone family. It constitutes the initial step in the hypothalamic–pituitary–gonadal axis.

Arcuate nucleus

The arcuate nucleus of the hypothalamus is an aggregation of neurons in the mediobasal hypothalamus, adjacent to the third ventricle and the median eminence. The arcuate nucleus includes several important and diverse populations of neurons that help mediate different neuroendocrine and physiological functions, including neuroendocrine neurons, centrally projecting neurons, and astrocytes. The populations of neurons found in the arcuate nucleus are based on the hormones they secrete or interact with and are responsible for hypothalamic function, such as regulating hormones released from the pituitary gland or secreting their own hormones. Neurons in this region are also responsible for integrating information and providing inputs to other nuclei in the hypothalamus or inputs to areas outside this region of the brain. These neurons, generated from the ventral part of the periventricular epithelium during embryonic development, locate dorsally in the hypothalamus, becoming part of the ventromedial hypothalamic region. The function of the arcuate nucleus relies on its diversity of neurons, but its central role is involved in homeostasis. The arcuate nucleus provides many physiological roles involved in feeding, metabolism, fertility, and cardiovascular regulation.

Tachykinin peptides

Tachykinin peptides are one of the largest families of neuropeptides, found from amphibians to mammals. They were so named due to their ability to rapidly induce contraction of gut tissue. The tachykinin family is characterized by a common C-terminal sequence, Phe-X-Gly-Leu-Met-NH2, where X is either an Aromatic or an Aliphatic amino acid. The genes that produce tachykinins encode precursor proteins called preprotachykinins, which are chopped apart into smaller peptides by posttranslational proteolytic processing. The genes also code for multiple splice forms that are made up of different sets of peptides.

Circumventricular organs Interfaces between the brain and the circulatory system

Circumventricular organs (CVOs) are structures in the brain characterized by their extensive and highly permeable capillaries, unlike those in the rest of the brain where there exists a blood–brain barrier (BBB) at the capillary level. Although the term "circumventricular organs" was originally proposed in 1958 by Austrian anatomist Helmut O. Hofer concerning structures around the brain ventricular system, the penetration of blood-borne dyes into small specific CVO regions was discovered in the early 20th century. The permeable CVOs enabling rapid neurohumoral exchange include the subfornical organ (SFO), the area postrema (AP), the vascular organ of lamina terminalis, the median eminence, the pituitary neural lobe, and the pineal gland.

The periventricular nucleus is a thin sheet of small neurons located in the wall of the third ventricle, a composite structure of the hypothalamus. It functions in analgesia.

Kisspeptin

Kisspeptins are proteins encoded by the KISS1 gene in humans. Kisspeptins are ligands of the G-protein coupled receptor, GPR54. Kiss1 was originally identified as a human metastasis suppressor gene that has the ability to suppress melanoma and breast cancer metastasis. Kisspeptin-GPR54 signaling has an important role in initiating secretion of gonadotropin-releasing hormone (GnRH) at puberty, the extent of which is an area of ongoing research. Gonadotropin-releasing hormone is released from the hypothalamus to act on the anterior pituitary triggering the release of luteinizing hormone (LH), and follicle stimulating hormone (FSH). These gonadotropic hormones lead to sexual maturation and gametogenesis. Disrupting GPR54 signaling can cause hypogonadotrophic hypogonadism in rodents and humans. The Kiss1 gene is located on chromosome 1. It is transcribed in the brain, adrenal gland, and pancreas.

Neurokinin 1 (NK1) antagonists (-pitants) are a novel class of medications that possesses unique antidepressant, anxiolytic, and antiemetic properties. NK-1 antagonists boost the efficacy of 5-HT3 antagonists to prevent nausea and vomiting. The discovery of neurokinin 1 (NK1) receptor antagonists was a turning point in the prevention of nausea and vomiting associated with cancer chemotherapy.

Neurokinin A Chemical compound

Neurokinin A (NKA), formerly known as Substance K, is a neurologically active peptide translated from the pre-protachykinin gene. Neurokinin A has many excitatory effects on mammalian nervous systems and is also influential on the mammalian inflammatory and pain responses.

Tachykinin receptor 1 Protein-coding gene in the species Homo sapiens

The tachykinin receptor 1 (TACR1) also known as neurokinin 1 receptor (NK1R) or substance P receptor (SPR) is a G protein coupled receptor found in the central nervous system and peripheral nervous system. The endogenous ligand for this receptor is Substance P, although it has some affinity for other tachykinins. The protein is the product of the TACR1 gene.

KiSS1-derived peptide receptor Mammalian protein found in Homo sapiens

The KiSS1-derived peptide receptor is a G protein-coupled receptor which binds the peptide hormone kisspeptin (metastin). Kisspeptin is encoded by the metastasis suppressor gene KISS1, which is expressed in a variety of endocrine and gonadal tissues. Activation of the kisspeptin receptor is linked to the phospholipase C and inositol trisphosphate second messenger cascades inside the cell.

Tachykinin receptor 3 Protein-coding gene in the species Homo sapiens

Tachykinin receptor 3, also known as TACR3, is a protein which in humans is encoded by the TACR3 gene.

TAC3

Tachykinin-3 is a protein that in humans is encoded by the TAC3 gene.

TAC1

Preprotachykinin-1,, is a precursor protein that in humans is encoded by the TAC1 gene.

Puberty is the process of physical changes through which a child's body matures into an adult body capable of sexual reproduction. It is initiated by hormonal signals from the brain to the gonads: the ovaries in a girl, the testes in a boy. In response to the signals, the gonads produce hormones that stimulate libido and the growth, function, and transformation of the brain, bones, muscle, blood, skin, hair, breasts, and sex organs. Physical growth—height and weight—accelerates in the first half of puberty and is completed when an adult body has been developed. Before puberty, the external sex organs, known as primary sexual characteristics, are sex characteristics that distinguish boys and girls. Puberty leads to sexual dimorphism through the development of the secondary sex characteristics, which further distinguish the sexes.

Fezolinetant Chemical compound

Fezolinetant (INN; former developmental code name ESN-364) is a small-molecule, orally active, selective neurokinin-3 (NK3) receptor antagonist which is under development by Ogeda (formerly Euroscreen) for the treatment of sex hormone-related disorders. As of May 2017, it has completed phase I and phase IIa clinical trials for hot flashes in postmenopausal women. Phase IIa trials in polycystic ovary syndrome patients are ongoing. In April 2017, it was announced that Ogeda would be acquired by Astellas Pharma.

Kisspeptin, neurokinin B, and dynorphin (KNDy) neurons are neurons in the hypothalamus of the brain that are central to the hormonal control of reproduction.

Gonadotropin-inhibitory hormone (GnIH) is a RFamide-related peptide coded by the NPVF gene in mammals.

References

  1. 1 2 Goodman, R.L; Coolen, L.M; Lehman, M.N (July 2014). "A Role for Neurokinin B in Pulsatile GnRH Secretion in the Ewe". Neuroendocrinology. 99 (1): 18–32. doi:10.1159/000355285. PMC   3976461 . PMID   24008670.
  2. ↑ Navarro, VM (2013). "Interactions between kisspeptins and neurokinin B". Adv Exp Med Biol. Advances in Experimental Medicine and Biology. 784: 325–347. doi:10.1007/978-1-4614-6199-9_15. ISBN   978-1-4614-6198-2. PMC   3858905 . PMID   23550013.
  3. ↑ Rie, Sakamoto; hisao, Osada; Yoshinori, Litsuka; Kentarou, Masuda; Kenshi, Kaku; Katsuyoshi, Seki; Souei, Sekiya (17 Apr 2003). "Profile of neurokinin B concentrations in maternal and cord blood in normal pregnancy". Clinical Endocrinology. 58 (5): 597–600. doi:10.1046/j.1365-2265.2003.01758.x. PMID   12699441. S2CID   30312551.
  4. 1 2 3 4 5 6 Lehman, Michael; Coolen, Lique; Goodman, Robert (August 2010). "Minireview: Kisspeptin/Neurokinin B/ Dynorphin Cells of the Arcuate Nucleus: A central Node in the Control of Gonadotorpin-Releasing Hormone Secretion". Endocrinology. 151 (8): 3479–3489. doi:10.1210/en.2010-0022. PMC   2940527 . PMID   20501670.
  5. ↑ Hasimoto, Tadashi; Uchida, Yoshiki; Okimura, Keiko; Kurosawa, Katsuro (1986). "Synthesis of Neurokinin B analogs and Their Activities as Agonists and Antagonists". Chem.Pharm.
  6. 1 2 3 4 5 6 7 Navarro, VM (2013). "Interactions between kisspeptins and neurokinin B". Adv Exp Med Biol. Advances in Experimental Medicine and Biology. 784: 325–347. doi:10.1007/978-1-4614-6199-9_15. ISBN   978-1-4614-6198-2. PMC   3858905 . PMID   23550013.
  7. 1 2 "Preeclampsia". babycenter.
  8. 1 2 3 Page, Nigel M (2010). "Neurokinin B and pre-eclampsia: a decade of discovery". Reproductive Biology and Endocrinology. 8 (1): 4. doi:10.1186/1477-7827-8-4. PMC   2817650 . PMID   20074343.
  9. ↑ "Tac2 Tachykinin 2". NCBI. Retrieved 23 April 2015.
  10. 1 2 Rance, Naomi E.; Bruce, Tami R. (1994). "Neurokinin B Gene Expression Is Increased in the Arcuate Nucleus of Ovariectomized Rats". Neuroendocrinology. 60 (4): 337–345. doi:10.1159/000126768. PMID   7529897.
  11. ↑ Ramaswamy, Suresh; Seminara, Stephanie; Barkat, Ali; Phillipe, Ciofi; Amin, Nisar; Plant, Tony (May 24, 2010). "Neurokinin B stimulates GnRH release in the Male Monkey and is Colocalized with Kisspeptin in the Arcuate Nucleus". Endocrinology. 151 (9): 4494–4503. doi:10.1210/en.2010-0223. PMC   2940495 . PMID   20573725.
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