Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: HUMANGGP:035231 (NKB)
 244 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Reproductive function is driven by the hormonal interplay between the gonads and brain-pituitary axis. Gonadotropin-releasing hormone (GnRH) is released in a pulsatile manner, which is critical for the attainment and maintenance of fertility, however, GnRH neurons lack the ability to directly respond to most regulatory factors, and a hierarchical upstream neuronal network governs its secretion. We and others proposed a model in which Kiss1 neurons in the arcuate nucleus (ARC), so called KNDy neurons, release kisspeptin (a potent GnRH secretagogue) in a pulsatile manner to drive GnRH pulses under the coordinated autosynaptic action of its cotransmitters, the tachykinin neurokinin B (NKB, stimulatory) and dynorphin (inhibitory). Numerous genetic and pharmacological studies support this model; however, additional regulatory mechanisms (upstream of KNDy neurons) and alternative pathways of GnRH secretion (kisspeptin-independent) exist, but remain ill defined. In this aspect, attention to other members of the tachykinin family, namely substance P (SP) and neurokinin A (NKA), has recently been rekindled. Even though there are still major gaps in our knowledge about the functional significance of these systems, substantial evidence, as discussed below, is placing tachykinin signaling as an important pathway for the awakening of the reproductive axis and the onset of puberty to physiological GnRH secretion and maintenance of fertility in adulthood.
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PMID:Expanding the Role of Tachykinins in the Neuroendocrine Control of Reproduction. 2775 72

Kisspeptin (KISS1; encoded by Kiss1) neurons in the arcuate nucleus (ARC) coexpress tachykinin 3 (TAC3; also known as neurokinin B) and dynorphin A (PDYN). Accordingly, they are termed KNDy neurons and considered to be crucial in generating pulsatile release of gonadotropin-releasing hormone. Accumulating evidence suggests that Kiss1 and Tac3 are negatively regulated by estrogen. However, it has not been fully determined whether and how estrogen modulates Pdyn and PDYN. Here, we examined the expression of Pdyn mRNA and PDYN by in situ hybridization and immunohistochemistry, respectively, in the ARC of female rats after ovariectomy (OVX) and OVX plus low- or high-dose beta-estradiol (E2) replacement. We also investigated the effect of E2 on expression of Kiss1, KISS1, Tac3, and TAC3. Furthermore, colocalization of PDYN and estrogen receptor alpha (ESR1) was determined. Subsequently, we found that low-dose E2 treatment had no effect on Pdyn mRNA-expressing cells, but increased PDYN-immunoreactive (ir) cell numbers. In contrast, high-dose E2 treatment resulted in prominent reductions in both Pdyn mRNA-expressing and PDYN-ir cell numbers. Changes induced by low or high doses of E2 were similarly observed in the expression of Kiss1, KISS1, Tac3, and TAC3. The majority of PDYN-ir neurons coexpressed ESR1 in all groups. Our results indicate that E2 regulates the expression of PDYN, as well as KISS1 and TAC3, with regulation by E2 differing according to its levels.
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PMID:Distinct dynorphin expression patterns with low- and high-dose estrogen treatment in the arcuate nucleus of female rats. 2906 89

In human patients, loss-of-function mutations in the genes encoding kisspeptin (KISS1) and neurokinin B (NKB) and their receptors (KISS1R and NK3R, respectively) result in an abnormal timing of puberty or the absence of puberty. To understand the neuroendocrine mechanism of puberty, we investigated the contribution of kisspeptin and NKB signaling to the pubertal increase in GnRH release using rhesus monkeys as a model. Direct measurements of GnRH and kisspeptin in the median eminence of the hypothalamus with infusion of agonists and antagonists for kisspeptin and NKB reveal that kisspeptin and NKB signaling stimulate GnRH release independently or collaboratively by forming kisspeptin and NKB neuronal networks depending on the developmental age. For example, while in prepubertal females, kisspeptin and NKB signaling independently stimulate GnRH release, in pubertal females, the formation of a collaborative kisspeptin and NKB network further accelerates the pubertal increase in GnRH release. It is speculated that the collaborative mechanism between kisspeptin and NKB signaling to GnRH neurons is necessary for the complex reproductive function in females.
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PMID:Role of Kisspeptin and Neurokinin B in Puberty in Female Non-Human Primates. 2968 89

The pubertal transition of gonadotropin secretion in pigs is metabolically gated. Kisspeptin (KISS1) and neurokinin B (NKB) are coexpressed in neurons within the arcuate nucleus of the hypothalamus (ARC) and are thought to play an important role in the integration of nutrition and metabolic state with the reproductive neuroendocrine axis. The hypothesis that circulating concentrations of luteinizing hormone (LH) and expression of KISS1 and tachykinin 3(TAC3, encodes NKB) in the ARC of female pigs are reduced with negative energy balance was tested using ovariectomized, prepubertal gilts fed to either gain or lose body weight. Restricted feeding of ovariectomized gilts caused a rapid and sustained metabolic response characterized by reduced concentrations of plasma urea nitrogen, insulin, leptin, and insulin-like growth factor-1 and elevated concentrations of free fatty acids. The secretory pattern of LH shifted from one of low amplitude to one of high amplitude, which caused overall circulating concentrations of LH to be greater in restricted gilts. Nutrient-restricted gilts had greater expression of follicle-stimulating hormone and gonadotropin-releasing hormone receptor, but not LH in the anterior pituitary gland. Expression of KISS1 in the ARC was not affected by dietary treatment, but expression of TAC3 was greater in restricted gilts. These data are consistent with the idea that hypothalamic expression of KISS1 is correlated with the number of LH pulse in pig, and further indicate that amplitude of LH pulses may be regulated by NKB in the gilt.
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PMID:Energy balance affects pulsatile secretion of luteinizing hormone from the adenohypophesis and expression of neurokinin B in the hypothalamus of ovariectomized gilts. 3010 Dec 93

The tachykinin neurokinin B (NKB, Tac2) is critical for proper GnRH release in mammals, however, the role of the other tachykinins, such as substance P (SP) and neurokinin A (NKA) in reproduction, is still not well understood. In this study, we demonstrate that NKA controls the timing of puberty onset (similar to NKB and SP) and stimulates LH release in adulthood through NKB-independent (but kisspeptin-dependent) mechanisms in the presence of sex steroids. Furthermore, this is achieved, at least in part, through the autosynaptic activation of Tac1 neurons, which express NK2R (Tacr2), the receptor for NKA. Conversely, in the absence of sex steroids, as observed in ovariectomy, NKA inhibits LH through a mechanism that requires the presence of functional receptors for NKB and dynorphin (NK3R and KOR, respectively). Moreover, the ability of NKA to modulate LH secretion is absent in Kiss1KO mice, suggesting that its action occurs upstream of Kiss1 neurons. Overall, we demonstrate that NKA signaling is a critical component in the central control of reproduction, by contributing to the indirect regulation of kisspeptin release.
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PMID:Characterization of the Role of NKA in the Control of Puberty Onset and Gonadotropin Release in the Female Mouse. 3150 89

A single male domestic shorthair cat that did not complete puberty was reported. At four years of age, it still had primary dentition, testicular hypoplasia, and was relatively small for its age. We hypothesized that the phenotype might have been due to an inherited form of hypogonadotropic hypogonadism (HH). We sequenced the genome of the affected cat and compared the data to 38 genomes from control cats. A search for private variants in 40 candidate genes associated with human HH revealed a single protein-changing variant in the affected cat. It was located in the TAC3 gene encoding tachykinin 3, a precursor protein of the signaling molecule neurokinin B, which is known to play a role in sexual development. TAC3 variants have been reported in human patients with HH. The identified feline variant, TAC3:c.220G>A or p.(Val74Met), affects a moderately conserved region of the precursor protein, 11 residues away from the mature neurokinin B sequence. The affected cat was homozygous for the mutant allele. In a cohort of 171 randomly sampled cats, 169 were homozygous for the wildtype allele and 2 were heterozygous. These data tentatively suggest that the identified TAC3 variant might have caused the suppression of puberty in the affected cat.
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PMID:A TAC3 Missense Variant in a Domestic Shorthair Cat with Testicular Hypoplasia and Persistent Primary Dentition. 3161 56

Damaraland mole rats (Fukomys damarensis) are cooperatively breeding, subterranean mammals, which exhibit high reproductive skew. Reproduction is monopolized by the dominant female of the group, while subordinates are physiologically suppressed. The blockade of reproduction results from an inhibition of ovulation, which is caused by inadequate secretion of luteinizing hormone (LH) from the pituitary, which in turn might be brought about by a disruption of the normal GnRH secretion from the hypothalamus. The neuropeptides dynorphin and neurokinin B are expressed together with kisspeptin in a subpopulation of neurons in the arcuate nucleus (ARC). This neuron population is termed KNDy neurons and is considered to constitute the GnRH pulse generator. To assess whether dynorphin (encoded by the Pdyn gene) and neurokinin B (NKB, encoded by the Tac3 gene) are involved in the mechanism of reproductive suppression we investigated the distribution and gene expression of Pdyn and Tac3 by means of in situ hybridisation in wild-caught female Damaraland mole-rats with different reproductive status. In both reproductive phenotypes, substantial Pdyn expression was found in several brain regions of the telencephalon including the cerebral cortex, the striatum, the hippocampus, the amygdala and the olfactory tubercle. Within the hypothalamus Pdyn expression occurred in the paraventricular nucleus, the dorsomedial nucleus, the supraoptic nucleus, the ventromedial nucleus and the ARC. Prominent Tac3 expression was found in the habenula, the bed nucleus of the stria terminalis, the cerebral cortex, the striatum, the hippocampus, the amygdala, the dorsomedial nucleus, the ARC and the lateral mammillary nucleus. Quantification of the gene expression levels in the ARC revealed decreased Pdyn and increased Tac3 expression in breeding compared to nonbreeding females. This suggests that both neuropeptides play a role in the regulation of reproduction in Damaraland mole-rats. Their exact role in mediating the inhibition of GnRH release in nonbreeding females remains to be determined.
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PMID:Reproductive status-dependent dynorphin and neurokinin B gene expression in female Damaraland mole-rats. 3166 32

The Tacr3 gene encodes tachykinin receptor 3 (NK3R), which belongs to the tachykinin receptor family. This family of proteins includes typical G protein-coupled receptors and belongs to the rhodopsin subfamily. NK3R functions by binding to its high-affinity ligand, neurokinin B(NKB). The role of Tacr3/NK3R in growth and reproduction has been extensively studied, but Tacr3/NK3R is also widely expressed in the nervous system from the spinal cord to the brain and is involved in both physiological and pathological processes in the nervous system, including mood disorders, chronic pain, learning and memory deficiencies, Alzheimer's disease, Parkinson's disease, addiction-related processes, hypoxic-ischemic encephalopathy, body fluid management, neural development, and schizophrenia. Here, we summarize the structure of NK3R/NKB and its cellular signaling as well as the expression of Tacr3/NK3R in the nervous system, and we provide a comprehensive summary of the role of Tacr3/NK3R in neurological diseases, including reproduction-related disorders and other neurological diseases. At the end of this review, we propose the hypothesis that Tacr3/NK3R mediates a variety of brain functions by affecting the excitability of different neurons with specific functions. On the basis of this "excited or not" hypothesis, more studies related to Tacr3 should be carried out in other nervous system diseases in order to better understand the biological roles of Tacr3.
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PMID:Tacr3/NK3R: Beyond Their Roles in Reproduction. 3292 72


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