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Aromatic amino acids in the finger domain of the FMRFamide-gated Na\(^+\) channel are involved in the FMRFamide recognition and the activation

  • Ion Channels, Receptors and Transporters
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Abstract

FMRFamide-gated Na\(^+\) channel (FaNaC) is a member of the DEG/ENaC family and activated by a neuropeptide, FMRFamide. Structural information about the FMRFamide-dependent gating is, however, still elusive. Because two phenylalanines of FMRFamide are essential for the activation of FaNaC, we hypothesized that aromatic-aromatic interaction between FaNaC and FMRFamide is critical for FMRFamide recognition and/or the activation gating. Here, we focused on eight conserved aromatic residues in the finger domain of FaNaCs and tested our hypothesis by mutagenic analysis and in silico docking simulations. The mutation of conserved aromatic residues in the finger domain reduced the FMRFamide potency, suggesting that the conserved aromatic residues are involved in the FMRFamide-dependent activation. The kinetics of the FMRFamide-gated currents were also modified substantially in some mutants. Some results of docking simulations were consistent with a hypothesis that the aromatic-aromatic interaction between the aromatic residues in FaNaC and FMRFamide is involved in the FMRFamide recognition. Collectively, our results suggest that the conserved aromatic residues in the finger domain of FaNaC are important determinants of the ligand recognition and/or the activation gating in FaNaC.

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The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Funding

This work was supported by JSPS KAKENHI Grant Number JP15K07149.

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Authors and Affiliations

  1. Laboratory of Neurobiology, Graduate School of Integrated Arts and Sciences, Hiroshima University, Higashi-Hiroshima, Japan

    Yasuo Furukawa & Iori Tagashira

  2. Laboratory of Neurobiology, Graduate School of Integrated Sciences of Life, Hiroshima University, Kagamiyama 1-7-1, Higashi-Hiroshima, 739-8521, Japan

    Yasuo Furukawa

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  1. Yasuo Furukawa
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Contributions

YF conceived research; YF designed experiments; YF and IT made mutant channels; IT performed electophysiological experiments by TEVC. YF performed electrophysiological experiments by COVC; IT and YF analyzed data; YF performed the homology modeling and the docking simulations. YF wrote a paper; IT and YF approved the final version of the paper.

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Correspondence to Yasuo Furukawa.

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All animal experiments were approved by the Hiroshima University Animal Research Committee (No. G20-1), and performed in accordance with the guidelines for the Japanese Association of Laboratory Animal Science and the Animal Experimentation of Hiroshima University.

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The authors declare no competing interests.

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Furukawa, Y., Tagashira, I. Aromatic amino acids in the finger domain of the FMRFamide-gated Na\(^+\) channel are involved in the FMRFamide recognition and the activation. Pflugers Arch - Eur J Physiol 475, 975–993 (2023). https://doi.org/10.1007/s00424-023-02817-9

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