Functional analysis of calcium channels related to intracellular stress signal transduction in bipolar disorder

2021 Fiscal Year Final Research Report

• Project/Area Number: 18K07594
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52030:Psychiatry-related
• Research Institution: University of Yamanashi
• Principal Investigator: Uemura Takuji 山梨大学, 大学院総合研究部, 講師 (60377497)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Keywords: CACNA1C / TRPC3 / リチウム / 酸化ストレス / 細胞内カルシウム濃度 / 細胞膜電位

Outline of Final Research Achievements

Our research focus is on the functional interaction among calcium channels related to intracellular stress signal pathway in bipolar disorder (BD). To confirm the function of SNP rs1006737 (G→A) located within the CACNA1C gene associated with BD, we created SNP rs1006737 AA cells (CACNA1C AA cells) using genome editing technique with CRISPR/Cas9 in human glioblastoma, YKG-1 cells. Both CACNA1C and TRPC3 expression were increased in CACNA1C AA cells, compared with the wild type of YKG-1 cells (WT). Additionally, hydrogen peroxide - stimulated Ca2+ mobilization and membrane potential were altered in this cell model compared with WT. Our study reveals that genetic variation in CACNA1C affects both CACNA1C and TRPC3 expression, intracellular Ca2+ homeostasis and membrane potential.

Free Research Field

分子精神医学

Academic Significance and Societal Importance of the Research Achievements

複数のゲノムワイド関連解析で、CACNA1C遺伝子内に存在するSNP rs1006737は双極性障害と強い関連を認める。本研究は、CACNA1CとTRPC3の相互作用におけるSNP rs1006737の役割を同定し、リチウムの薬理学的作用を含めたストレスシグナル伝達破綻に関わるカルシウムチャネルの役割を詳細に検討することを目的としており、双極性障害の発症機序の解明に貢献するだけでなく、バイオマーカーの樹立などの臨床応用・発展へと繋げていくことを目指している。