Involvements of Cav1.3 in the generation of a sustained inward Na+ current in sinoatrial node cells

• Project/Area Number: 26460295
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General physiology
• Research Institution: Shiga University of Medical Science
• Principal Investigator: Toyoda Futoshi 滋賀医科大学, 医学部, 助教 (90324574)
• Co-Investigator(Kenkyū-buntansha): 松浦 博 滋賀医科大学, 医学部, 教授 (60238962) ; 林 維光 滋賀医科大学, 医学部, 助教 (80242973)
• Project Period (FY): 2014-04-01 – 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 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2014: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 心臓 / ペースメーカー活動 / イオンチャネル / ペースメーカー / 洞房結節細胞 / 電気生理学 / 心筋細胞

Outline of Final Research Achievements

The sustained inward Na+ current has been recorded in sinoatrial node cells and put foreword as a potential pacemaker current in the heart. However, molecular determinants for Ist remain unknown. The present study has investigated the involvement of Cav1.3 L-type Ca2+ channels in the generation of Ist. We found that genetic ablation of Cav1.3 resulted in total abolition of Ist. Then we applied a next-generation sequencing approach to examine potential splicing and RNA editing of Cav1.3 in sinoatrial node, but failed to provide evidence for the presence of variants that can produce a Na current. These results raise the possibility that Cav1.3 is functionally coupled to unknown Na-permable pathway to mediate Ist in cardiac pacemaker cells.

Research Products

• [Int'l Joint Research] CNRS/IGF(フランス)
• [Int'l Joint Research] CNRSゲノム機能研究所(フランス)
• [Int'l Joint Research] インスブルック大学(オーストリア)
• [Journal Article] CaV1.3 L-type Ca2+ channel contributes to the heartbeat by generating a dihydropyridine-sensitive persistent Na+ current (2017)
  • Author(s): Toyoda Futoshi、Mesirca Pietro、Dubel Stefan、Ding Wei-Guang、Striessnig Joerg、Mangoni Matteo E.、Matsuura Hiroshi
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 7869-7869
  • DOI: 10.1038/s41598-017-08191-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Heterogeneous functional expression of the sustained inward Na+ current in guinea pig sinoatrial node cells (2017)
  • Author(s): Toyoda Futoshi、Wei-Guang Ding、Matsuura Hiroshi
  • Journal Title: Pflugers Archiv - European Journal of Physiology Volume: 470 Issue: 3 Pages: 481-490
  • DOI: 10.1007/s00424-017-2091-y
  • Peer Reviewed
• [Journal Article] Regulation of human cardiac Kv1.5 channels by extracellular acidification. (2016)
  • Author(s): Wang S, Ding WG, Bai JY, Toyoda F, Wei MJ, Matsuura H.
  • Journal Title: Pflugers Arch Volume: 468 Pages: 1885-1894
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Activation of a chondrocyte volume-sensitive Cl(-) conductance prior to macroscopic cartilage lesion formation in the rabbit knee anterior cruciate ligament transection osteoarthritis model (2016)
  • Author(s): Kumagai K, Toyoda F, Staunton CA, Maeda T, Okumura N, Matsuura H, Matsusue Y, Imai S, Barrett-Jolley R
  • Journal Title: Osteoarthritis Cartilage Volume: 24 Issue: 10 Pages: 1786-1794
  • DOI: 10.1016/j.joca.2016.05.019
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Lidocaine induces ROCK-dependent membrane blebbing and subsequent cell death in rabbit articular chondrocytes. (2016)
  • Author(s): Maeda T, Toyoda F, Imai S, Tanigawa H, Kumagai K, Matsuura H, Matsusue Y.
  • Journal Title: J Orthop Res Volume: 34 Issue: 5 Pages: 754-762
  • DOI: 10.1002/jor.23092
  • Peer Reviewed
• [Journal Article] Novel mutations in the gene for α-subunit of retinal cone cyclic nucleotide-gated channels in a Japanese patient with congenital achromatopsia. (2016)
  • Author(s): Kuniyoshi K, Muraki-Oda S, Ueyama H, Toyoda F, Sakuramoto H, Ogita H, Irifune M, Yamamoto S, Nakao A, Tsunoda K, Iwata T, Ohji M, Shimomura Y.
  • Journal Title: Jpn J Ophthalmol Volume: 60 Issue: 3 Pages: 187-197
  • DOI: 10.1007/s10384-016-0424-6
  • Peer Reviewed / Open Access
• [Journal Article] Phosphatidylinositol4-phosphate 5-kinase prevents the decrease in the HERG potassium current induced by Gq protein-coupled receptor stimulation (2015)
  • Author(s): Kubo T, Ding, W-G, Toyoda F, Fujii Y, Omatsu-Kabe M, Matsuura H
  • Journal Title: J Pharmacol Sci Volume: 127 Issue: 1 Pages: 127-134
  • DOI: 10.1016/j.jphs.2014.11.013
  • Peer Reviewed / Open Access
• [Journal Article] Long QT Syndrome Type8: Novel CACNA1C Mutations Causing QT Prolongation and Variant Phenotypes. (2014)
  • Author(s): Fukuyama M, Wang Q, Kato K, Ohno S, Ding WG, Toyoda F, Itoh H, Kimura H, Makiyama T, Ito M, Matsuura H, Horie M.
  • Journal Title: Europace. Volume: in press Issue: 12 Pages: 1828-37
  • DOI: 10.1093/europace/euu063
  • Peer Reviewed / Open Access
• [Presentation] A potential link between L-type CaV1.3 channel and TRPM4 Ca2+-activated nonselective cation channel in cardiac pacemaker cells (2018)
  • Author(s): Toyoda F, Ding WG, Matsuura H
  • Organizer: 第95回日本生理学会
• [Presentation] Does TRPM4 Ca2+-activated nonselective cation channel mediate the sustained inward Na+ current in mouse sinoatrial node cells? (2017)
  • Author(s): Toyoda F, Matsuura H
  • Organizer: 第９４回日本生理学会大会
  • Place of Presentation: 浜松市
  • Year and Date: 2017-03-28
• [Presentation] 心臓ペースメーカー細胞のL型Ca2+チャネルはNa+電流を誘発して拍動リズムの形成に寄与する (2017)
  • Author(s): 豊田 太、丁 維光、松浦 博
  • Organizer: 2017年度生命科学系学会合同年次大会
• [Presentation] Dihydropyridine-sensitive Na+ current contributes to the diastolic depolarization in cardiac pacemaker cells. (2016)
  • Author(s): Toyoda F, Ding WG, Matsuura H
  • Organizer: 第93回日本生理学会大会
  • Place of Presentation: 札幌
  • Year and Date: 2016-03-22
• [Presentation] CaV1.3 mediates not only L-type Ca2+ current but also the sustained inward Na+ current in mouse sinoatrial node cells. (2015)
  • Author(s): Futoshi Toyoda, Pietro Mesirca, Stefan Dubel, Wei-Guang Ding, Joerg Striessnig, Matteo E. Mangoni, Hiroshi Matsuura
  • Organizer: 2nd European Calcium Channel Conference
  • Place of Presentation: Alpbach, Austria
  • Year and Date: 2015-05-13 – 2015-05-16
• [Presentation] CaV1.3 mediates calcium currents and a sustained inward Na+ current in mouse cardiac pacemaker cells. (2015)
  • Author(s): Toyoda F, Mesirca P, Dubel S, Ding WG, Striessnig J, Mangoni ME, Matsuura H
  • Organizer: 2nd European Calcium Channel Conference
  • Place of Presentation: Alpbach, Austria
  • Year and Date: 2015-05-13
  • Int'l Joint Research
• [Presentation] Functional relationships between L-type CaV1.3 channel and the sustained inward Na+ current in cardiac pacemaker cells (2015)
  • Author(s): Futoshi Toyoda, Wei-Guang Ding, Hiroshi Matsuura
  • Organizer: 第92回日本生理学会大会
  • Place of Presentation: 神戸
  • Year and Date: 2015-03-21 – 2015-03-23