Elucidation of TRPV1 channel function in the mechanism of malignant hyperthermia

2023 Fiscal Year Final Research Report

• Project/Area Number: 22K16602
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 55050:Anesthesiology-related
• Research Institution: Hiroshima University
• Principal Investigator: Miyoshi Hirotsugu 広島大学, 病院(医), 講師 (50645364)
• Project Period (FY): 2022-04-01 – 2024-03-31
• Keywords: 悪性高熱症 / TRPV1 / 遺伝子解析 / 遺伝子変異

Outline of Final Research Achievements

Malignant hyperthermia is an autosomal dominant inherited muscle disease. Exposure to volatile inhalation anesthetics in patients predisposed to malignant hyperthermia can be fatal due to hypermetabolism and hyperthermia. The main cause of malignant hyperthermia is said to be genetic mutation of ryanodine receptor type 1. On the other hand, it is known that half of patients with malignant hyperthermia do not have this receptor gene mutation. This suggests that malignant hyperthermia is caused by genetic mutations other than the ryanodine receptor. In this study, we focused on the TRPV1 gene mutation newly identified in patients with malignant hyperthermia and investigated the relationship between this gene mutation and malignant hyperthermia. We created TRPV1 knock-in mice and examined whether general anesthetics induce malignant hyperthermia. According to the research results to date, the investigated TRPV1 gene mutations do not cause malignant hyperthermia.

Free Research Field

麻酔科学

Academic Significance and Societal Importance of the Research Achievements

全静脈麻酔による全身麻酔により悪性高熱症を発症した患者からTRPV1（Q261P）の遺伝子変異が見つかったことに注目し、悪性高熱症の発症機序にこのTRPV1の遺伝子変異が悪性高熱症の機序に関与しているかどうかを調べた。TRPV1の遺伝子変異のノックインマウスを作成し揮発性吸入麻酔薬への曝露により悪性高熱症を発症するかどうかを検証したが、いずれの濃度のセボフルラン、デスフルラン、イソフルランにも特異的な反応を示さず、悪性高熱症の特徴である心拍数の上昇や体温の上昇は見られなかった。一方で、このTRPV1の変異はMyotubeにおいてCapsaicinへの反応性が完全に欠如することが分かった。