A study on the functional structures in the extracellular domain of a peptide-gated Na+ channel

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K06337
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 44050:Animal physiological chemistry, physiology and behavioral biology-related
• Research Institution: Hiroshima University
• Principal Investigator: Furukawa Yasuo 広島大学, 統合生命科学研究科(総), 教授 (40209169)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: イオンチャネル / ペプチド

Outline of Final Research Achievements

To understand the molecular mechanisms of the FMRFamide-gated Na+ channel (FaNaC), we focused on the extracellular domain of the channel which must have peptide binding site(s) as well as the linking structure for the activation of the transmembrane pore. There are seven SS-bonds in the extracellular domain of FaNaC. We tested the function of each SS-bond one by one and found that the SS-bonds which are necessary to maintain the thumb domain of FaNaC are indispensable for the normal function of the channel. We next mutated several residues in the finger domain and found that several aromatic residues are important for the activation of the channel. We also made the 3D-model of FaNaC and carried out the docking simulation of FMRFamide. The results are consistent with the results of mutagenic experiments, suggesting that some of the aromatic residues are determinants of the FMRFamide binding site.

Free Research Field

神経生物学

Academic Significance and Societal Importance of the Research Achievements

本研究では、軟体動物で発見されたペプチド作動性チャネル（FaNaC）の細胞外ドメイン構造の働きに焦点をあて、これまで未解明であったFaNaCの活性化に必要な細胞外ドメイン構造の一端を明らかにした。ペプチド作動性チャネルは一部の無脊椎動物でしかみつかっていないが、チャネル構造からみると、ヒトの腎臓におけるNa+吸収を司る上皮性Na+チャネル（ENaC）の仲間である。従って、FaNaCのチャネル構造と機能の理解が進むことは、ヒトの血圧調節に関わる因子の一つであるENaCの機能を探る研究に、比較生物学的視点を提供するものにもなるはずである。