| Co-Investigator(Kenkyū-buntansha) |
MINEGISHI Takashi GUNMA UNIVERSITY, Medicine, Professor, 大学院・医学系研究科, 教授 (00209842)
ABE Yumiko GUNMA UNIVERSITY, Medicine, Research Associate, 大学院・医学系研究科, 助手 (70261857)
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| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2005: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2004: ¥2,100,000 (Direct Cost: ¥2,100,000)
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| Research Abstract |
Follitropin (FSH), lutropin (LH), chorionic gonadotropin (CG) and thyrotropin (TSH) constitute the glycoprotein hormones, made of a common a subunit and specific 8 subunits sharing more than 40% aminoacid sequence identities. Although the corresponding glycoprotein hormone receptors [GPHrs : FSHr, LH/CGr, TSHr] display also about 40% sequence identity in their hormone binding domains, co-evolution of the hormonereceptor couples resulted in the establishment of tight specificity barriers, preventing promiscuous activation under normal physiological conditions.
Recently, a crystal structure became available for a complex of single-chain FSH bound to a large N-terminal fragment of the FSH-R ectodomain. Therefore, we have started to investigate the heterogeneity at 307 and 680. There are Thr/Thr, Ala/Thr and Ala/Ala 307 genotype, and Asn/Asn, Ser/Asn and Ser/Ser 680 genotype. We plan to analyze the relationship genotype and ovarian sensitivity to exogenesis FSH during ovulation induction.
A coimmunoprecipitation experiment clearly showed that hLHR(exon 9) and constitutively inactivate mutant-LHRs, which stay in the ER, form an association with the human follitropin (FSH)-receptor (hFSHR). This suggests that in the presence of mutant-LHR, hFSHR, which is trapped in the ER and associated with hLHR-(exon 9), is unable to come up to the plasma membrane. This phenomenon is specific among gonadotropin receptors because human TSH receptor failed to be coimmunoprecipitated. Furthermore, this receptor complex attenuated the hFSHR receptor protein level within the cells, which impaired cAMP production.
The relationship between hormone-induced and mutation-induced FSH-R activation is an interesting and major problem remaining to be elucidated.
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