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Questions And Answer

• Structure

  Tetrapod neurokinin B are composed of 10 amino acids. In several teleosts such as the zebrafish and salmon,NKBa consists of 10 amino acids, whereas NKBb, another zebrafish neurokinin B subtype, has 24 amino acids. NKF is composed of 13 aa. All tac3-derived peptides share the C-terminal Phe-X-Gly-Leu-Met-amide tachykinin (TK) sequence.In particular, NKBs and NKFs almost exclusively contain Val at the “X” position, as seeninNKA family peptides. Comparedwith NKA, NKB possesses no basic amino acid (Lys or Arg). These motifs and residues have been shown to play crucial roles in receptor activation and binding selectivity.;

• Gene, mRNA, and precursor

  Neurokinin B is encoded in tac3 (or pptB). Vertebrate tac3 is organized by seven or eight exons. Most tetrapod NKB is present as a single copy in the fifth exon. To date, several splicing variants have been shown to be generated from tac3 in mammals while only NKB is produced from these precursors. In several teleosts including zebrafish and salmon, two tac3, tac3a and tac3b, are present. For instance, zebrafish tac3a encodes one 10-amino acid NKBa and one NKF, whereas one 24-aa NKBb and one additional NKF are encoded by tac3b, where only the second Asn of tac3a-derived NKF is replaced with Asp.;

• Receptors

  TK receptors, namely NK1 (TACR1), NK2 (TACR2), and NK3 (TACR3), belong to the class A G protein-coupled receptor family. NKB displays selective affinity to NK3. In most teleosts, two subtypes, namely tac3ra and tac3rb, are conserved. NKF activated human NK3, and zebrafish TACR3a and TACR3b comparable to mammalian NKB or zebrafish NKBa, whereas zebrafish NKBb is 100- to 100-fold less potent than these NKB family peptides.
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• Signal transduction pathway

  Mammalian and zebrafish NK3, expressed in Xenopus oocytes or cultured cells, triggers intracellular calcium mobilization and cAMP production in response to their selective ligands, followed by the activation of PKC, MAPK, and ERK phosphorylation in a cell- or tissuespecific manner.;

• Agonists and Antagonists

  A number of mammalian NK3 agonists such as senktide and [MePhe7]neurokinin B are commercially available.  A wide variety of NK3-competitive antagonists such as osanetant and talnetant are commercially available. It should be noted that almost no evidence has been provided for the pharmacological agonists or antagonists for mammalian NK3 on nonvertebrate homologs.;

• Biological functions

  In mammals, NK3 is distributed in the brain, hypothalamus (including the median eminence), kidney, lung, placenta, prostate, testis, muscle, intestine, uterus, and the sperm midpiece as well as weakly in the proximal region of the sperm flagellum. In zebrafish, tacr3a is expressed mainly in the pituitary, also during embryonic development. A low tacr3b expression was detected in the midbrain and testis. In mammals, circulating NKB via the enhancement of expression of the tac3 gene was elevated in the placenta of preeclampsia women, but not in the placenta of women in normotensive pregnancy. Moreover, NKB participates in the regulation of GnRH pulse generation in the mammalian hypothalamus-pituitary-gonad axis. This GnRH release system is in part regulated by NKB in concert with kisspeptin yielded by KNDy neurons, whereas the involvement of non-KNDy NKB neurons or other kisspeptin-free NKB neurons in the stimulation of GnRH release is also reported. NK3R is also suggested to influence alcohol intake and behavioral/neurochemical responses to cocaine. In prepubertal zebrafish, estradiol treatment upregulates tac3a gene expression as well as kiss1, kiss2, and gnrh3.  Furthermore, in sexually mature zebrafish, the intraperitoneal injection of NKBa and NKF resulted in the secretion of luteinizing hormone.;

• Clinical implications

  NKB is highly likely to be involved in preeclampsia in the placenta and familial hypogonadotropic hypognadism.;

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