アポトーシス制御分子Ｂｃｌ－２とＩＰ３受容体による神経可塑性と神経突起伸展の制御

Research Project

Project/Area Number	13F03793
Research Category	Grant-in-Aid for JSPS Fellows
Allocation Type	Single-year Grants
Section	外国
Research Field	神経化学・神経薬理学
Research Institution	Institute of Physical and Chemical Research
Principal Investigator	御子柴克彦国立研究開発法人理化学研究所, 脳科学総合研究センター, チームリーダー (30051840)
Co-Investigator(Kenkyū-buntansha)	BONNEAU BENJAMIN 国立研究開発法人理化学研究所, 脳科学総合研究センター, 外国人特別研究員 BONNEAU Benjamin 独立行政法人理化学研究所, 脳科学総合研究センター, 外国人特別研究員 BONNEAU B. R.
Project Period (FY)	2013-04-01 – 2016-03-31
Project Status	Completed (Fiscal Year 2015)
Budget Amount *help	¥2,300,000 (Direct Cost: ¥2,300,000) Fiscal Year 2015: ¥600,000 (Direct Cost: ¥600,000) Fiscal Year 2014: ¥1,100,000 (Direct Cost: ¥1,100,000) Fiscal Year 2013: ¥600,000 (Direct Cost: ¥600,000)
Keywords	IP3R / calcium / Bol-2 / IRBIT / apoptosis / Bcl-2
Outline of Annual Research Achievements	Our research focuses on the interplay between IRBIT, an IP3R-interacting protein discovered in our lab, and the Bcl-2 homolog, Bcl2L10. The zebrafish ortholog of Bcl2L10, Nrz inhibits IP3 fixation on IP3R by interacting with the IP3-binding domain (IP3BD) of the receptor. This mechanism is similar to the one of IRBIT so we studied if these two proteins can be associated to regulate IP3R activity and apoptosis. We have firstly confirmed that Bcl2L10, as its zebrafish ortholog, is able to interact with the IP3BD of IP3R and significantly reduced IP3-induced Ca2+ release. In a second time, we showed that IRBIT and Bcl2L10 interact together and that they bind simultaneously with IP3R. Bcl2L10 strengthens IRBIT interaction with IP3R and the 2 proteins have a synergic effect on IP3-induced Ca2+ release regulation. Interestingly we found that IRBIT and Bcl2L10 are both localized at the mitochondria-associated ER membranes and belong to a protein complex containing IP3R and VDAC. This complex is essential for Ca2+ transfer to mitochondria and play a key role in apoptosis. We found that cells lacking IRBIT are more resistant to diverse apoptotic stress. During apoptosis, IRBIT is dephosphorylated which induces its displacement together with Bcl2L10 from ER membranes. IRBIT dephosphorylation then promotes Ca2+ transfer to the mitochondria which facilitates apoptosis. Finally, we found that IRBIT KO reduces the contact between ER and mitochondria. Then by facilitating ER-mitochondria contact and inhibiting Bcl2L10 interaction with IP3R IRBIT seems to promote Ca2+-dependent apoptosis.
Research Progress Status	27年度が最終年度であるため、記入しない。
Strategy for Future Research Activity	27年度が最終年度であるため、記入しない。