Investigation on possible link between Ist and CaV1.3 RNA editing

2013 Fiscal Year Final Research Report

• Project/Area Number: 23590258
• 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): MATSUURA Hiroshi 滋賀医科大学, 医学部, 教授 (60238962) ; DING Wei-guang 滋賀医科大学, 医学部, 助教 (80242973)
• Project Period (FY): 2011 – 2013
• Keywords: 心臓 / ペースメーカー / 洞房結節 / イオンチャネル

Research Abstract

The sustained inward Na+ current (Ist) in sinoatrial node (SAN) pacemaker cells has been suggested to contribute to the pacemaker activity, although unknown molecular correlates of this current limits the understanding of its significance in the pacemaker activity. The purpose of this study was 1) to examine the relationship between L-type Ca2+ channel CaV1.3 subunit and Ist in their functional expression levels, and 2) to identify the RNA editing-mediated CaV1.3 variants. The density of Ist was positively correlated with the magnitude of L-type Ca2+ current (ICa,L). In knock-out mice with disruption of CaV1.3, ICa,L was significantly reduced, which was accompanied by a complete loss of Ist. Comprehensive analysis of CaV1.3 transcripts using the second generation sequencer revealed the presence of rare variants with residue changes in the Ca2+ selectivity filter. These findings suggest that Ist is mediated by CaV1.3 variants Ist in SAN pacemaker cells.

Research Products

• [Journal Article] Improved functional expression of human cardiac kv1.5 channels and trafficking-defective mutants by low temperature treatment (2014)
  • Author(s): Ding WG, Xie Y, Toyoda F, Matsuura H
  • Journal Title: PLoS One Volume: 9巻 (eCollection 2014) Pages: e92923
  • DOI: 10.1371/journal.pone.0092923,10.1016/j.bbadis.2011.07.011
  • Peer Reviewed
• [Journal Article] The G-protein-gated K^+ channel, IKACh, is required for regulation of pacemaker activity and recovery of resting heart rate after sympathetic stimulation (2013)
  • Author(s): Mesirca P, Marger L, Toyoda F, Rizzetto R, Audoubert M, Dubel S, Torrente AG, Difrancesco ML, Muller JC, Leoni AL, Couette B, Nargeot J, Clapham DE, Wickman K, Mangoni ME
  • Journal Title: J Gen Physiol Volume: 142巻 Pages: 113-126
  • DOI: 10.1085/jgp.201310996
  • Peer Reviewed
• [Journal Article] 17β-Oestradiol inhibits doxorubicin-induced apoptosis via block of the volume-sensitive Cl^- current in rabbit articular chondrocytes (2012)
  • Author(s): Kumagai K, Imai S, Toyoda F, Okumura N, Isoya E, Matsuura H, Matsusue Y
  • Journal Title: Br J Pharmacol Volume: 166巻 Pages: 702-720
  • DOI: 10.1111/j.1476-5381.2011.01802.x
  • Peer Reviewed
• [Journal Article] Identification and functional characterization of KCNQ1 mutations around the exon 7-intron 7 junction affecting the splicing process (2011)
  • Author(s): Tsuji-Wakisaka K, Akao M, Ishii TM, Ashihara T, Makiyama T, Ohno S, Toyoda F, Dochi K, Matsuura H, Horie M
  • Journal Title: Biochim Biophys Acta Volume: 1812巻 Pages: 1452-1459
  • Peer Reviewed
• [Presentation] CaV1.3 is involved in Ist in mouse SAN cells (2014)
  • Author(s): 豊田太、Mesirca Pietro、Dubel Stefan、丁維光、Striessnig Joerg、Mangoni E Matteo、松浦博
  • Organizer: 第91回日本生理学会大会
  • Place of Presentation: 鹿児島
  • Year and Date: 20140300
• [Presentation] Positive correlation between Ist and ICa,L in guinea-pig sinoatrial node cells (2013)
  • Author(s): 豊田太、丁維光、松浦博
  • Organizer: 第90回日本生理学会大会
  • Place of Presentation: 東京
  • Year and Date: 20130300
• [Presentation] Cellular heterogeneity of the sustained inward Na^+ current in guinea-pig sinoatrial node (2012)
  • Author(s): 豊田太、丁維光、松浦博
  • Organizer: 第89回日本生理学会大会
  • Place of Presentation: 松本市
  • Year and Date: 20120300