S-palmitoylation as a novel regulatory machinery for HCN channels

• Project/Area Number: 15K07017
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Functional biochemistry
• Research Institution: National Center of Neurology and Psychiatry (2016-2017); Kurume University (2015)
• Principal Investigator: Itoh Masayuki 国立研究開発法人国立精神・神経医療研究センター, 神経研究所 病態生化学研究部, 科研費研究員 (20442535)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2016: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2015: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
• Keywords: HCNチャネル / パルミトイル化 / 翻訳後修飾 / KCNHチャネル / イオンチャネル / ZDHHCタンパク質

Outline of Final Research Achievements

In this study, we found that among hyperpolarization-activated cyclic nucleotide-modulated channel family (HCN1-4), HCN1, HCN2 and HCN4, but not HCN3, are the targets of S-palmitoylation. Further, we identified palmitoylating enzymes that regulate the palmitoylation of HCN2 channel. Multiple Zdhhc-family of palmitoylating enzymes significantly increased the palmitoylation of HCN1 and HCN2 proteins. Especially, 5 Zdhhc proteins (Zdhhc2, Zdhhc3, Zdhhc7, Zdhhc15, and Zdhhc20) augmented the palmitoylation of HCN2 protein approximately over 10-fold of control level. When Zdhhc3 and Zdhhc7 were co-expressed with HCN2 in Xenopus oocytes, these enzymes reduced the current amplitude of HCN2 without affecting transport of HCN2 to plasma membrane. In addition, we found that among KCNH voltage gated K+ channel family, Kv10.1, Kv11.1 and Kv12.2 are novel targets of S-palmitoylation.

Research Products

• [Journal Article] Evolutionary acquisition and divergence of vertebrate HCN2 palmitoylation. (2017)
  • Author(s): Itoh M, Kaizuka T, Hayashi T
  • Journal Title: Neurotransmitter Volume: 4
  • DOI: 10.14800/nt.1603
  • Peer Reviewed / Open Access
• [Journal Article] The hyperpolarization-activated cyclic nucleotide-gated (HCN) channels contain multiple S-palmitoylation sites (2016)
  • Author(s): Itoh, M., Ishihara, K., Nakashima, N., Takano, M.
  • Journal Title: J Physiol Sci Volume: 66 Issue: 3 Pages: 241-8
  • DOI: 10.1007/s12576-015-0420-5
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Clinical Concentrations of Local Anesthetics Bupivacaine and Lidocaine Differentially Inhibit Human Kir2.x Inward Rectifier K+ Channels (2016)
  • Author(s): Nakahira, K., Oshita, K., Itoh, M., Takano, M., Sakaguchi, Y., Ishihara, K.
  • Journal Title: Anesth Analg Volume: 122 Issue: 4 Pages: 1038-47
  • DOI: 10.1213/ane.0000000000001137
  • Peer Reviewed
• [Presentation] パルミトイル化によるAMPA型グルタミン受容体の制御とその異常に伴うてんかん発作 (2017)
  • Author(s): 伊藤政之，山下真梨子，奥野浩行，阿部学，山崎真弥，夏目里恵，崎村建司，星野幹雄，三品昌美，林崇
  • Organizer: 第90回日本薬理学会年会
  • Place of Presentation: 長崎
  • Year and Date: 2017-03-16
• [Presentation] パルミトイル化サイト欠失型AMPA受容体ノックインマウスにおける興奮性神経活動の亢進と発作感受性の上昇 (2017)
  • Author(s): 伊藤政之，山下真梨子，山田大輔，奥野浩行，阿部学，山崎真弥，夏目里恵，金子雅規，貝塚利恵，崎村建司，関口正幸，和田圭司，星野幹雄，三品昌美，林崇
  • Organizer: 第40回日本神経科学大会
• [Presentation] AMPA受容体パルミトイル化による興奮性シナプスの機能維持とその異常に伴うてんかん発作 (2016)
  • Author(s): 伊藤政之，山下真梨子，奥野浩行，阿部学，山崎真弥，夏目里恵，崎村建司，星野幹雄，三品昌美，林崇
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2016-12-02