ArticleFASEB journal : official publication of the Federation of American Societies for Experimental Biology2014
TACR3 mutations disrupt NK3R function through distinct mechanisms in GnRH-deficient patients.
Article in FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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10 citing papers in PubMed, 13 citations in OpenAlex.
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- Noval insights and therapeutic strategies for tumor-induced kidney pathologies.Journal of experimental & clinical cancer research : CR · 2024Article
- Tachykinin receptor 3 in the lateral habenula alleviates pain and anxiety comorbidity in mice.Frontiers in immunology · 2023Article
- Functional Rescue of Inactivating Mutations of the Human Neurokinin 3 Receptor Using Pharmacological Chaperones.International journal of molecular sciences · 2022Article
- Analysis of Expression Profiles of CircRNA and MiRNA in Oviduct during the Follicular and Luteal Phases of Sheep with Two Fecundity (Animals : an open access journal from MDPI · 2021Article
- A novel stopgain mutation c.G992A (p.W331X) in TACR3 gene was identified in nonobstructive azoospermia by targeted next-generation sequencing.Journal of clinical laboratory analysis · 2019Article
- Computational Analysis of Missense Variants of G Protein-Coupled Receptors Involved in the Neuroendocrine Regulation of Reproduction.Neuroendocrinology · 2016Article
- Substance p regulates puberty onset and fertility in the female mouse.Endocrinology · 2015Article
- KISS1R signals independently of Gαq/11 and triggers LH secretion via the β-arrestin pathway in the male mouse.Endocrinology · 2014Article
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Authors and funding
11 authors at 5 institutions in 2 countries.
Funding
Abstract
Neurokinin B (NKB) and its G-protein-coupled receptor, NK3R, have been implicated in the neuroendocrine control of GnRH release; however, little is known about the structure-function relationship of this ligand-receptor pair. Moreover, loss-of-function NK3R mutations cause GnRH deficiency in humans. Using missense mutations in NK3R we previously identified in patients with GnRH deficiency, we demonstrate that Y256H and Y315C NK3R mutations in the fifth and sixth transmembrane domains (TM5 and TM6), resulted in reduced whole-cell (79.3±7.2%) or plasma membrane (67.3±7.3%) levels, respectively, compared with wild-type (WT) NK3R, with near complete loss of inositol phosphate (IP) signaling, implicating these domains in receptor trafficking, processing, and/or stability. We further demonstrate in a FRET-based assay that R295S NK3R, in the third intracellular loop (IL3), bound NKB but impaired dissociation of Gq-protein subunits from the receptor compared with WT NK3R, which showed a 10.0 ± 1.3% reduction in FRET ratios following ligand binding, indicating activation of Gq-protein signaling. Interestingly, R295S NK3R, identified in the heterozygous state in a GnRH-deficient patient, also interfered with dissociation of G proteins and IP signaling from wild-type NK3R, indicative of dominant-negative effects. Collectively, our data illustrate roles for TM5 and TM6 in NK3R trafficking and ligand binding and for IL3 in NK3R signaling.
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