Identification of novel drug on the regulation of abnormal ion selectivity of channels: toward the therapy for channelopathy

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K07304
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 48030:Pharmacology-related
• Research Institution: Wakayama Medical University (2021-2022); National Institute for Physiological Sciences (2020)
• Principal Investigator: Chen I-Shan 和歌山県立医科大学, 医学部, 講師 (40757770)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: イオン選択性

Outline of Final Research Achievements

Abnormal ion selectivity due to genetic mutations in GIRK channels causes cell death due to excessive Na+ and Ca2+ influx. Some congenital diseases are caused by such disorders of ion regulation function. In the present study, we investigated pathological mutants of GIRK2 to reveal the mechanism of abnormal ion selectivity and identify novel drugs. Our results demonstrate that a novel Na+, Li+-permeable pathway (the second pathway) exists in an selectivity filter (SF) mutant, GIRK2 G156S, in addition to the conventional ion conducting pathway formed by SF. To identify the inhibitors of the second permeation pathway, we screened a compound library and found some novel drugs that selective inhibits the abnormal currents. These novel drugs are potential to be applied to the regulation of ion selectivity.

Free Research Field

イオンチャネル・受容体

Academic Significance and Societal Importance of the Research Achievements

これまで、K+チャネルの遺伝子変異による疾患における異常なイオン流入は、イオン選択性フィルタのゆがみ等が原因だと考えられているが、本研究で、チャネルの第二のイオン透過路の存在が明らかになったことから、この第二のイオン透過路を阻害することにより異常なイオン流入を防ぐ新規治療薬の開発につながることが期待される。