Functional coupling between calcium-sensing receptor and ion channel in pulmonary hypertension

• Project/Area Number: 25860068
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pharmacology in pharmacy
• Research Institution: Kinjo Gakuin University
• Principal Investigator: YAMAMURA Aya 金城学院大学, 薬学部, 助教 (40633219)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 肺高血圧 / カルシウム感受性受容体 / イオンチャネル / 血管 / 肺動脈 / 平滑筋 / TRPチャネル / カルシウム / イメージング / 受容体

Outline of Final Research Achievements

Sustained vasoconstriction and vascular remodeling due to pulmonary arterial smooth muscle cell (PASMC) proliferation are key pathogenic events for idiopathic pulmonary arterial hypertension (IPAH). We have previously shown that calcium-sensing receptor (CaSR) is upregulated in IPAH-PASMCs and contributes to enhanced calcium response. In this study, we examined whether non-selective cation channel is involved in enhanced calcium influx followed by CaSR activation in IPAH-PASMCs. The expression levels of TRPC channel in IPAH-PASMCs were greater than in normal PASMCs. Knockdown of TRPC channel in IPAH-PASMCs with siRNA attenuated the CaSR-mediated calcium increase. In conclusion, the extracellular calcium-induced calcium increase due to functional coupling between CaSR and TRPC channel is a novel pathogenic mechanism contributing to the augmented calcium influx and excessive PASMC proliferation in IPAH patients.

Research Products

• [Journal Article] Notch Activation of Ca2+ Signaling Mediates Hypoxic Pulmonary Vasoconstriction and Pulmonary Hypertension (2015)
  • Author(s): Smith KA, Voiriot G, Tang H, Fraidenburg DR, Song S, Yamamura H, Yamamura A, Guo Q, Wan J, Pohl NM, Tauseef M, Bodmer R, Ocorr K, Thistlethwaite PA, Haddad GG, Powell FL, Makino A, Mehta D, Yuan JX
  • Journal Title: Am J Respir Cell Mol Biol Volume: in press Issue: 3 Pages: 355-367
  • DOI: 10.1165/rcmb.2014-0235oc
  • Peer Reviewed
• [Journal Article] Flow shear stress enhances intracellular Ca2+ signaling in pulmonary artery smooth muscle cells from patients with pulmonary arterial hypertension. (2014)
  • Author(s): Song S, Yamamura A, Yamamura H, Ayon RJ, Smith KA, Tang H, Makino A, Yuan JX.
  • Journal Title: Am J Physiol Cell Physiol Volume: 307(4)
  • Peer Reviewed
• [Journal Article] Inhibition of the Ca(2+)-sensing receptor rescues pulmonary hypertension in rats and mice. (2014)
  • Author(s): Guo Q, Huang JA, Yamamura A, Yamamura H, Zimnicka AM, Fernandez R, Yuan JX.
  • Journal Title: Hypertens Res. Volume: 37(2) Issue: 2 Pages: 116-24
  • DOI: 10.1038/hr.2013.129
  • Peer Reviewed
• [Journal Article] Activation of Notch signaling by short-term treatment with Jagged-1 enhances store-operated Ca2+ entry in human pulmonary arterial smooth muscle cells. (2014)
  • Author(s): Yamamura H, Yamamura A, Ko EA, Pohl NM, Smith KA, Zeifman A, Powell FL, Thistlethwaite PA, Yuan JX.
  • Journal Title: Am J Physiol Cell Physiol. Volume: 306(9) Issue: 9 Pages: C871-C878
  • DOI: 10.1152/ajpcell.00221.2013
  • Peer Reviewed
• [Journal Article] Pathological function of Ca²⁺-sensing receptor in pulmonary arterial hypertension (2014)
  • Author(s): Yamamura A.
  • Journal Title: Journal of Smooth Muscle Research Volume: 50 Issue: 0 Pages: 8-17
  • DOI: 10.1540/jsmr.50.8
  • NAID: 130003391244
  • ISSN: 0916-8737, 1884-8796
  • Peer Reviewed
• [Journal Article] カルシウム感受性受容体の血管生理機能と病態発現変化 (2014)
  • Author(s): 山村彩
  • Journal Title: 血管 Volume: 37 Pages: 9-20
  • Peer Reviewed
• [Journal Article] Protective Effects of Fluvoxamine against Ischemia/Reperfusion Injury in Isolated, Perfused Guinea-Pig Hearts (2014)
  • Author(s): T. Muto, H. Usuda, A. Yamamura, K. Yoshida, A. Ohashi, K. Mitsui-Saitoh, J. Sakai, Y. Sugimoto, H. Mizutani, T. Nonogaki, Y. Hotta
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 37 Issue: 5 Pages: 731-739
  • DOI: 10.1248/bpb.b13-00552
  • NAID: 130004147319
  • ISSN: 0918-6158, 1347-5215
  • Peer Reviewed / Open Access
• [Journal Article] Enhanced Ca²⁺-sensing Receptor Function in Pulmonary Hypertension (2013)
  • Author(s): Yamamura A, Yamamura H, Yuan JX.
  • Journal Title: YAKUGAKU ZASSHI Volume: 133 Issue: 12 Pages: 1351-1359
  • DOI: 10.1248/yakushi.13-00228-3
  • NAID: 130003382290
  • ISSN: 0031-6903, 1347-5231
  • Year and Date: 2013-12-01
  • Peer Reviewed
• [Journal Article] Dihydropyridine Ca2+ channel blockers increase cytosolic [Ca2+] by activating Ca2+-sensing receptors in pulmonary arterial smooth muscle cells (2013)
  • Author(s): Yamamura A
  • Journal Title: Circ Res Volume: 112 Issue: 4 Pages: 640-50
  • DOI: 10.1161/circresaha.113.300897
  • Peer Reviewed
• [Journal Article] Functional Characterization of Voltage-dependent Ca2+ Channels in Mouse Pulmonary Arterial Smooth Muscle Cells: Divergent Effect of ROS. (2013)
  • Author(s): Ko EA
  • Journal Title: Am J Physiol Cell Physiol Volume: in press Issue: 11 Pages: C1042-C1052
  • DOI: 10.1152/ajpcell.00304.2012
  • Peer Reviewed
• [Journal Article] Chronic hypoxia selectively enhances L- and T-type voltage-dependent Ca2+ channel activity in pulmonary artery by upregulating Cav1.2 and Cav3.2. (2013)
  • Author(s): Wan J, Yamamura A, Zimnicka AM, Voiriot G, Smith KA, Tang H, Ayon RJ, Choudhury MS, Ko EA, Wang J, Wang C, Makino A, Yuan JX.
  • Journal Title: Am J Physiol Lung Cell Mol Physiol. Volume: 305(2) Issue: 2 Pages: L154-L164
  • DOI: 10.1152/ajplung.00313.2012
  • Peer Reviewed
• [Presentation] 肺動脈性肺高血圧症におけるニフェジピンの増悪効果 (2015)
  • Author(s): 山村彩、森志穂、堀井千裕、平工明里、大原直樹、塚本喜久雄、Jason X.-J. Yuan
  • Organizer: 日本薬学会第135年会
  • Place of Presentation: 兵庫医療大学
  • Year and Date: 2015-03-26
• [Presentation] Pulmonary arterial hypertension (2015)
  • Author(s): Aya Yamamura
  • Organizer: The 88th Annual Meeting of The Japanese Pharmacological Society
  • Place of Presentation: Nagoya Congress Center
  • Year and Date: 2015-03-20
  • Invited
• [Presentation] Nifedipine activates Ca2+-sensing receptors upregulated in pulmonary hypertension (2015)
  • Author(s): Aya Yamamura, Naoki Ohara, Kikuo Tsukamoto, Hisao Yamamura, Jason X.-J. Yuan
  • Organizer: The 88th Annual Meeting of The Japanese Pharmacological Society
  • Place of Presentation: Nagoya Congress Center
  • Year and Date: 2015-03-18
• [Presentation] Micro-RNA-mediated regulation of K+ channels in pulmonary arterial smooth muscle (2015)
  • Author(s): Ramon J. Ayon, Nicole M. Pohl, Aya Yamamura, Hisao Yamamura, Ayako Makino, Jason X.-J. Yuan
  • Organizer: International Symposium on Ion channels, transporters, and small molecules as key regulators of homeostatic systems
  • Place of Presentation: Nagoya Congress Center
  • Year and Date: 2015-03-17
  • Invited
• [Presentation] モノクロタリン誘発性肺高血圧症ラットにおけるニフェジピンの増悪効果 (2014)
  • Author(s): 山村彩、森志穂、堀井千裕、平工明里、大原直樹、塚本喜久雄、山村寿男、Jason X.-J. Yuan
  • Organizer: 日本病院薬剤師会東海ブロック・日本薬学会東海支部合同学術大会2014
  • Place of Presentation: 静岡県立大学
  • Year and Date: 2014-11-09
• [Presentation] ジヒドロピリジン系Ca2+チャネルブロッカーは肺高血圧症で機能亢進するCa2+感受性受容体を活性化する (2014)
  • Author(s): 山村彩、山村寿男、Jason X.-J. Yuan
  • Organizer: 心血管膜輸送研究会2014
  • Place of Presentation: 生理学研究所
  • Year and Date: 2014-09-04
• [Presentation] 肺高血圧モデルラットの病態における週齢差の影響 (2014)
  • Author(s): 森志穂、堀井千裕、平工明里、塚本喜久雄、大原直樹、山村彩
  • Organizer: 次世代を担う創薬・医療薬理シンポジウム2014
  • Place of Presentation: 近畿大学
  • Year and Date: 2014-08-30
• [Presentation] 肺高血圧症で機能亢進するCa2+感受性受容体はジヒドロピリジン系Ca2+チャネルブロッカーによって活性化する (2014)
  • Author(s): 山村彩、平工明里、堀井千裕、塚本喜久雄、小崎康子、大原直樹、Jason X.-J. Yuan
  • Organizer: 第56回日本平滑筋学会総会
  • Place of Presentation: 新横浜プリンスホテル
  • Year and Date: 2014-08-07
• [Presentation] Ca2+感受性受容体に対するジヒドロピリジン系Ca2+チャネルブロッカーの効果 (2014)
  • Author(s): 山村彩、堀井千裕、平工明里、塚本喜久雄、小崎康子、大原直樹、山村寿男、Jason X.-J. Yuan
  • Organizer: 第60回日本薬学会東海支部総会・大会
  • Place of Presentation: 鈴鹿医療科学大学
  • Year and Date: 2014-07-05
• [Presentation] モノクロタリン誘発性肺高血圧症ラットにおけるカルシウム感受性受容体拮抗薬の効果
  • Author(s): 山村彩, 山村寿男, Qiang Guo, Adriana M. Zimnicka, 塚本喜久雄, 大原直樹, Jason X.-J. Yuan
  • Organizer: 第123回日本薬理学会近畿部会
  • Place of Presentation: 名古屋
• [Presentation] モノクロタリン誘発性肺高血圧症ラットにおける性ホルモンの影響
  • Author(s): 小林沙紀 , 塚本喜久雄 , 大原直樹 , 山村彩
  • Organizer: 次世代を担う創薬・医療薬理シンポジウム2013
  • Place of Presentation: 熊本
• [Presentation] 肺高血圧症モデル動物におけるカルシウム感受性受容体拮抗薬の効果
  • Author(s): 山村彩、山村寿男、Qiang Guo、Adriana M. Zimnicka、小崎康子、塚本喜久雄、Jason X.-J. Yuan
  • Organizer: 第59回日本薬学会東海支部大会
  • Place of Presentation: 名古屋
• [Presentation] カルシウム感受性受容体と肺高血圧症
  • Author(s): 山村彩、山村寿男、Jason X.-J. Yuan
  • Organizer: 第55回日本平滑筋学会総会
  • Place of Presentation: 旭川
  • Invited
• [Presentation] Enhanced Ca2+-sensing receptor function in idiopathic pulmonary arterial hypertension
  • Author(s): 山村彩
  • Organizer: 第55回日本平滑筋学会総会
  • Place of Presentation: 旭川
  • Invited
• [Presentation] 肺動脈性高血圧におけるCa2+感受性受容体とTRPC6チャネルの機能的連関
  • Author(s): 山村彩、平工明里、堀井千裕、塚本喜久雄、小崎康子、大原直樹、Jason X.-J. Yuan
  • Organizer: 日本薬学会第134年会
  • Place of Presentation: 熊本
• [Presentation] Functional coupling between Ca2+-sensing receptor and TRPC6 channel in pulmonary hypertension
  • Author(s): Aya Yamamura, Hisao Yamamura, Jason X.-J. Yuan
  • Organizer: The 91st Annual Meeting of the Physiological Society of Japan
  • Place of Presentation: Kagoshima
  • Invited
• [Presentation] Functional coupling of TRPC6 channel with Ca2+-sensing receptor in pulmonary hypertension
  • Author(s): Aya Yamamura, Kikuo Tsukamoto, Naoki Ohara, Jason X.-J. Yuan
  • Organizer: The 87th Annual Meeting of the Japanese Pharmacological Society
  • Place of Presentation: Sendai
• [Presentation] Enhanced Ca2+-sensing receptor function in idiopathic pulmonary arterial hypertension
  • Author(s): Aya Yamamura, Qiang Guo, Hisao Yamamura, Adriana M. Zimnicka, Nicole M. Pohl, Kimberly A. Smith, Ruby A. Fernandez, Amy Zeifman, Ayako Makino, Hui Dong, Jason X.-J. Yuan
  • Organizer: IUPS2013
  • Place of Presentation: Birmingham, UK
• [Remarks] 金城学院大学 学術研究データベース
  • URL: http://tdb.kinjo-u.ac.jp/search/index.php/search/teacher_info?teacherid=12847
• [Remarks] 金城学院大学 学術研究データベース
  • URL: http://tdb.kinjo-u.ac.jp/search/index.php/search/teacher_info?teacherid=12847