Effect of endothelin converting enzyme -1 on prutitus

• Project/Area Number: 25860424
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pain science
• Research Institution: Kyushu University
• Principal Investigator: NAKAHARA Makiko 九州大学, 医学(系)研究科(研究院), 助教 (80530120)
• 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: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: エンドセリン変換酵素 / かゆみ / エンドセリン

Outline of Final Research Achievements

Endothelin-1 (ET-1) evokes histamine-independent pruritus in mammals by activating its G protein-coupled receptor, Endothelin A receptor (ETAR). We identified neural endothelin-converting enzyme-1 (ECE-1) as a key regulator of ET-1-induced pruritus and neural signaling of itch. ETAR, ET-1 and ECE-1 are expressed and co-localize in murine DRG neurons and human skin nerves. In neurons of murine dorsal root ganglia neurons, ECE-1 inhibition prolonged ET-1-induced activation of extracellular signal regulated kinase1/2 (ERK1/2). ET-1-induced scratching behavior in mice was significantly augmented by ECE-1 inhibition and abrogated by ERK1/2 inhibition in vivo. Our results for the first time indicate that a neural peptidase, ECE-1, directly regulates endothelin-induced, histamine-independent pruritus in mice, and implicate the ET-1/ECE-1/ERK1/2 pathway as an important target to treat pruritus.

Research Products

• [Journal Article] Neural Peptidase Endothelin-converting Enzyme-1 regulates Endothelin-1-induced Pruritus (2014)
  • Author(s): Makiko Kido-Nakahara, Joerg Buddenkotte, Cordula Kempkes, Akihiko Ikoma, Ferda Cevikbas, Tasuku Akiyama, Frank Nunes, Stephan Seeliger, Burcu Hasdemir, Christian Mess, Timo Buhl, Mathias Sulk, Frank-Ulrich Muller, Dieter Metze, Nigel W. Bunnett, Earl Carstens, Aditi Bhargava, Masutaka Furue and Martin Steinhoff
  • Journal Title: The Journal of Clinical Investigation Volume: 124 Issue: 6 Pages: 2683-2695
  • DOI: 10.1172/jci67323
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] エンドセリン変換酵素－１はエンドセリン－１による痒みを制御する (2014)
  • Author(s): Makiko Kido-Nakahara, Joerg Buddenkotte, Cordula Kempkes, Akihiko Ikoma, Ferda Cevikbas, Tasuku Akiyama, Frank Nunes, Stephan Seeliger, Burcu Hasdemir, Christian Mess, Timo Buhl, Mathias Sulk, Frank-Ulrich Muller, Dieter Metze, Nigel W. Bunnett, Earl Carstens, Aditi Bhargava, Masutaka Furue and Martin Steinhoff
  • Organizer: 第２４回国際痒みシンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2014-10-18