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.
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.
Description
Vertebrate tachykinins encoded by TAC3 gene (Tac2 in
rodents). In 1983, Kangawa et al. isolated neurokinin B (NKB)
from the porcine spinal cord and elucidated the primary
sequence as Asp-Met-His-Asp-Phe-Phe-Val-Gly-Leu-Met-amide, followed by the characterization of other tetrapod NKB. In 2012, teleost NKB and its-gene-related
peptide, NKF, were identified.
Definition
ChEBI: Neurokinin B is a polypeptide. It is a mammalian neuropeptide of 10 amino acids that belongs to the tachykinin family is similar in structure and action to substance P and neurokinin A. It has the ability to excite neurons, dilate blood vessels, and contract smooth muscles, such as those in the urinary bladder and uterus.
Biochem/physiol Actions
Neurokinin B is a ten-residue peptide. It is an endogenous tachykinin agonist with preference for the NK-3 receptor. It is a potent bronchoconstrictor and may have a neuromodulatory role in the brain. Neurokinin B has a role in slow synaptic or non-synaptic communication.
References
[1] LAUFERR. Neurokinin B is a preferred agonist for a neuronal substance P receptor and its action is antagonized by enkephalin.[J]. Proceedings of the National Academy of Sciences of the United States of America, 1985, 82 21: 7444-7448. DOI:
10.1073/pnas.82.21.7444.
[2] RANCENAOMI E. Neurokinin B and the hypothalamic regulation of reproduction.[J]. Brain Research, 2010, 1364: 116-128. DOI:
10.1016/j.brainres.2010.08.059.
[3] MARIA ASMAT F. R M Ramzan. Exogenous Neurokinin B Administration May Have a Strong Effect on Negative Feedback Loop of Hypothalamic Pituitary Thyroid Axis[J]. International Journal of Peptide Research and Therapeutics, 2019, 26 1: 1259-1267. DOI:
10.1007/s10989-019-09925-0.
