TACR3 mutations disrupt NK3R function through distinct mechanisms in GnRH-deficient patients

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art_NOEL_TACR3_mutations_disrupt_NK3R_function_through_distinct_mechanisms_2014.PDF (392.66 KB)
Citações na Scopus
10
Tipo de produção
article
Data de publicação
2014
DOI
Scopus
Web of Science
PubMed
Título da Revista
ISSN da Revista
Título do Volume
Editora
FEDERATION AMER SOC EXP BIOL
Autores
NOEL, Sekoni D.
ABREU, Ana Paula
XU, Shuyun
MUYIDE, Titilayo
GIANETTI, Elena
CARROLL, Jessica
SEMINARA, Stephanie B.
CARROLL, Rona S.
Citação
FASEB JOURNAL, v.28, n.4, p.1924-1937, 2014
Projetos de Pesquisa
Unidades Organizacionais
Fascículo
Resumo
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 G(q)-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 G(q)-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.-Noel, S. D., Abreu, A. P., Xu, S., Muyide, T., Gianetti, E., Tusset, C., Carroll, J., Latronico, A. C., Seminara, S. B., Carroll, R. S., Kaiser, U. B. TACR3 mutations disrupt NK3R function through distinct mechanisms in GnRH-deficient patients.
Palavras-chave
tachykinins, GPCR, hypogonadotropic hypogonadism, neurokinin B
URI
https://observatorio.fm.usp.br/handle/OPI/7354
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Coleções
Artigos e Materiais de Revistas Científicas - FM/MCM
Artigos e Materiais de Revistas Científicas - LIM/42
Artigos e Materiais de Revistas Científicas - ODS/03