医学部 生理学講座

中條 浩一

ナカジョウ コウイチ  (Koichi Nakajo)

基本情報

所属
自治医科大学 医学部生理学講座 統合生理学部門 教授
学位
博士(学術)(東京大学)

研究者番号
80390699
ORCID ID
 https://orcid.org/0000-0003-0766-7281
J-GLOBAL ID
200901036408706842
researchmap会員ID
6000000396

外部リンク

学歴

 3

論文

 37
  • Alessandro Porro, Edoardo Armano, Federico Brandalise, Rebecca Appiani, Monica Beltrame, Andrea Saponaro, Clelia Dallanoce, Koichi Nakajo, Kaei Ryu, Roberta Leone, Gerhard Thiel, Marco Pallavicini, Anna Moroni, Cristiano Bolchi
    Journal of medicinal chemistry 2024年9月5日  査読有り
    Therapeutic drugs, whose bioactivity is hindered by a photoremovable cage, offer the advantage of spatiotemporal confinement of their action to the target diseased tissue with improved bioavailability and efficacy. Here, we have applied such an approach to ivabradine (IVA), a bradycardic agent indicated for angina pectoris and heart failure, acting as a specific HCN channel blocker. To overcome the side effects due to its poor discrimination among HCN channel subtypes (HCN1-4), we prepared a caged version of IVA linked to a photocleavable bromoquinolinylmethyl group (BHQ-IVA). We show that upon illumination with blue light (440 nm), BHQ-IVA releases active IVA that blocks HCN channel currents in vitro and exerts a bradycardic effect in vivo. Both BHQ-IVA and the cage are inactive. Caging is stable in aqueous medium and in the dark, and it does not impair aqueous solubility and cell permeation, indispensable for IVA activity. This approach allows for bypassing the poor subtype-specificity of IVA, expanding its prescription to HCN-related diseases besides cardiac.
  • Koichi Nakajo, Go Kasuya
    Physiological Reports 2024年3月  査読有り招待有り筆頭著者責任著者
  • Daichi Yamanouchi, Go Kasuya, Koichi Nakajo, Yoshiaki Kise, Osamu Nureki
    Molecular Cell 2023年11月29日  査読有り
  • Jiaying Liu, Go Kasuya, Buntaro Zempo, Koichi Nakajo
    Frontiers in Physiology 13 2022年6月30日  査読有り最終著者責任著者
    <jats:p>The HCN4 channel is essential for heart rate regulation in vertebrates by generating pacemaker potentials in the sinoatrial node. HCN4 channel abnormality may cause bradycardia and sick sinus syndrome, making it an important target for clinical research and drug discovery. The zebrafish is a popular animal model for cardiovascular research. They are potentially suitable for studying inherited heart diseases, including cardiac arrhythmia. However, it has not been determined how similar the ion channels that underlie cardiac automaticity are in zebrafish and humans. In the case of HCN4, humans have one gene, whereas zebrafish have two ortholog genes (<jats:italic>DrHCN4</jats:italic> and <jats:italic>DrHCN4L</jats:italic>; ‘Dr’ referring to <jats:italic>Danio rerio</jats:italic>). However, it is not known whether the two HCN4 channels have different physiological functions and roles in heart rate regulation. In this study, we characterized the biophysical properties of the two zebrafish HCN4 channels in <jats:italic>Xenopus</jats:italic> oocytes and compared them to those of the human HCN4 channel. We found that they showed different gating properties: DrHCN4L currents showed faster activation kinetics and a more positively shifted G-V curve than did DrHCN4 and human HCN4 currents. We made chimeric channels of DrHCN4 and DrHCN4L and found that cytoplasmic domains were determinants for the faster activation and the positively shifted G-V relationship in DrHCN4L. The use of a dominant-negative HCN4 mutant confirmed that DrHCN4 and DrHCN4L can form a heteromultimeric channel in <jats:italic>Xenopus</jats:italic> oocytes. Next, we confirmed that both are sensitive to common HCN channel inhibitors/blockers including Cs<jats:sup>+</jats:sup>, ivabradine, and ZD7288. These HCN inhibitors successfully lowered zebrafish heart rate during early embryonic stages. Finally, we knocked down the HCN4 genes using antisense morpholino and found that knocking down either or both of the HCN4 channels caused a temporal decrease in heart rate and tended to cause pericardial edema. These findings suggest that both DrHCN4 and DrHCN4L play a significant role in zebrafish heart rate regulation.</jats:p>

主要なMISC

 24

書籍等出版物

 1

講演・口頭発表等

 4

主要な担当経験のある科目(授業)

 3

主要な共同研究・競争的資金等の研究課題

 15