Evidence of the Importance of the First Intracellular Loop of Prokineticin Receptor 2 in Receptor Function

Autor(es)

Abreu, Ana Paula ^{[1, 2]} ; Noel, Sekoni D. ^[1] ; Xu, Shuyun ^[1] ; Carroll, Rona S. ^[1] ; Latronico, Ana Claudia ^[2] ; Kaiser, Ursula B. ^[1]

Afiliação do(s) autor(es)

^[1] Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens, Boston, MA 02115 - USA

^[2] Univ Sao Paulo, Sch Med, Teaching Hosp, Dev Endocrinol Unit, Lab Hormones & Mol Genet, BR-05403 Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: MOLECULAR ENDOCRINOLOGY; v. 26, n. 8, p. 1417-1427, AUG 2012.
• Citações Web of Science: 18

Resumo

Prokineticin receptors (PROKR) are G protein-coupled receptors (GPCR) that regulate diverse biological processes, including olfactory bulb neurogenesis and GnRH neuronal migration. Mutations in PROKR2 have been described in patients with varying degrees of GnRH deficiency and are located in diverse functional domains of the receptor. Our goal was to determine whether variants in the first intracellular loop (ICL1) of PROKR2 (R80C, R85C, and R85H) identified in patients with hypogonadotropic hypogonadism interfere with receptor function and to elucidate the mechanisms of these effects. Because of structural homology among GPCR, clarification of the role of ICL1 in PROKR2 activity may contribute to a better understanding of this domain across other GPCR. The effects of the ICL1 PROKR2 mutations on activation of signal transduction pathways, ligand binding, and receptor expression were evaluated. Our results indicated that the R85C and R85H PROKR2 mutations interfere only modestly with receptor function, whereas the R80C PROKR2 mutation leads to a marked reduction in receptor activity. Cotransfection of wild-type (WT) and R80C PROKR2 showed that the R80C mutant could exert a dominant negative effect on WT PROKR2 in vitro by interfering with WT receptor expression. In summary, we have shown the importance of Arg80 in ICL1 for PROKR2 expression and demonstrate that R80C PROKR2 exerts a dominant negative effect on WT PROKR2. (Molecular Endocrinology 26: 1417-1427, 2012) (AU)

• Processo FAPESP: 06/56753-3 - Pesquisa de mutações no gene do receptor da proquineticina 2 em pacientes com Síndrome de Kallmann
• Beneficiário: Ana Paula de Abreu e Silva
• Linha de fomento: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 05/04726-0 - Caracterização molecular das doenças endócrinas congênitas que afetam o crescimento e o desenvolvimento
• Beneficiário: Ana Claudia Latronico Xavier
• Linha de fomento: Auxílio à Pesquisa - Temático