Molecular mechanism of self-regulation of Cav1.2 channel by channel cytoplasmic fragments
| Project/Area Number |
19K07285
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Multi-year Fund |
|---|
| Section | 一般 |
|---|
| Review Section |
Basic Section 48020:Physiology-related
|
|---|
| Research Institution | Kagoshima University |
|---|
Principal Investigator |
Xu Jianjun 鹿児島大学, 医歯学域医学系, 講師 (10581689)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
亀山 正樹 鹿児島大学, 医歯学総合研究科, 客員研究員 (60150059)
|
|---|
| Project Period (FY) |
2019-04-01 – 2022-03-31
|
| Project Status |
Completed (Fiscal Year 2021)
|
| Budget Amount *help |
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
|
|---|
| Keywords | カルシムチャネル / 心筋細胞 / カルモジュリン / pull-down assay / パッチクランプ法 / 自己調節 / イオンチャネル / カルシムチャンネル / Pull-down assay / Calcium channel |
|---|
| Outline of Research at the Start |
Cardiac L-type Ca2+ channels(Cav1.2) are finely controlled within a narrow range of activity. Dysfunction of Cav1.2 channels in heart and brain leads to arrhythmia, heart failure and neuropsychiatric disorders. The present study aims to elucidate the mechanism of Cav1.2 regulation and try to explore the specific therapeutic targets for heart and brain diseases.
|
| Outline of Final Research Achievements |
In this study, we examined the interaction between cytoplasmic fragments of Cav1.2 channel, and elucidated the role of fragments in the regulation of the channel. Using pulldown assay, we examined CaM binding to N terminus (NT), proximal C terminus (CT1), the loop between repeat I-II, II-III and III-IV (LI-II, LII-III and LIII-IV). We found that at high Ca2+, CaM bound to CT1, NT and LI-II. C lobe of CaM had highest binding affinity for CT1 while N lobe for NT. There was no direct interaction between NT and CT1, however, N and C terminus were bridged by Ca2+/CaM with N lobe/N terminus and C lobe/C terminus interactions. In addition, there was a direct interaction between NT and LI-II, independent of Ca2+/CaM. The electrophysiological experiments with WT CaM (N lobe-C lobe) and its mutants N-N CaM (N lobe-N lobe), C-C CaM (C lobe-C lobe) indicates that C lobe CDI contributes to major CDI, while N lobe CDI is responsible for minor CDI. Both N and C lobe are required for complete CDI.
|
| Academic Significance and Societal Importance of the Research Achievements |
Cav1.2カルシウムチャネル(Cav1.2チャネル)は、心臓、脳、内分泌細胞、平滑筋で広く発現しており、その機能不全が心不全、不整脈、神経精神障害などの多系統障害を引き起こす可能性がある。 従って、Cav1.2チャネルの調節機構を解明することは、これらの疾患の新しい治療戦略を開発するために重要である。
|
Report
(4 results)
Research Products
(8 results)
-
-
-
-
-
[Journal Article] Properties of Calmodulin Binding to NaV1.2 IQ Motif and Its Autism-Associated Mutation R1902C2021
Author(s)
Jia Wanying, Liu Junyan, Yu Zhiyi, Zhang Xiaohong, Xu Xiaoxue, Wang Yuting, Gao Qinghua, Feng Rui, Wan Yujun, Xu Jianjun, Minobe Etsuko, Kameyama Masaki, Wang Wuyang, Guo Feng
-
Journal Title
Neurochemical Research
Volume: 46
Issue: 3
Pages: 523-534
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
-
-
-
