Calcium dysregulation by channelophay and pahological role in kidney podocyte

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K06872
• 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: University of Occupational and Environmental Health, Japan (2019-2020); Kyoto University (2018)
• Principal Investigator: Mori Masayuki 産業医科大学, 医学部, 教授 (80342640)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: イオンチャネル / チャネロパシー / カルシウム依存的不活性化 / 糸球体硬化症 / TRPC6 / Calmodulin / ポドサイト / ネフローゼ症候群

Outline of Final Research Achievements

TRPC6 is a nonselective cation channel, and mutations of this gene are associated with FSGS. These mutations are associated with TRPC6 current amplitude amplification and/or delay of the channel inactivation (gain-of-function phenotype). However, the mechanism of the gain-of-function in TRPC6 activity has not yet been clearly solved.　We performed electrophysiologic, biochemical, and biophysical experiments to elucidate the molecular mechanism underlying calmodulin (CaM)-mediated Ca2+-dependent inactivation (CDI) of TRPC6. The FSGS-associated TRPC6 mutations within the coiled-coil severely delayed CDI and often increased TRPC6 current amplitudes. The gain-of-function mechanism found in FSGS-causing mutations, TRPC6 can be explained by impairments of the CDI, caused by disruptions of TRPC's coiled-coil assembly and CaM bridge binding. The resulting excess Ca2+ may contribute to structural damage in the podocytes.

Free Research Field

分子生理学、生理化学

Academic Significance and Societal Importance of the Research Achievements

本研究グループは、カルシウムチャネルの一つTRPC6の活性にブレーキをかける、Ca(2+)依存的不活性化（Ca(2+)-dependent inactivation：CDI）と呼ばれる機構に関する研究を行い、その分子的基盤を得た。解析した5種類のFSGS型TRPC6全てにおいて分子構造体の異常を伴ったCDIの破綻を認めた。これらは、TRPC6のCDI分子機構を明らかにすると共にこのブレーキ機構の破綻がFSGS発症原因であるという新しい概念を提唱するもので、TRPC6の分子基盤、FSGSの診断、治療へ向けた重要な足がかりになると考えられた。