Neurotransmission of sensory information through CALHM ion channels

• Project/Area Number: 16K15181
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: General physiology
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: Taruno Akiyuki 京都府立医科大学, 医学(系)研究科(研究院), 教授 (20706824)
• Co-Investigator(Kenkyū-buntansha): 加塩 麻紀子 京都府立医科大学, 医学(系)研究科(研究院), 助教 (20631394)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: シナプス / イオンチャネル / CALHM / 味覚 / 神経伝達 / 翻訳後修飾 / 生理学 / 感覚系

Outline of Final Research Achievements

Using my original research tools, I analyzed function and expression of two ion channel subunits, CALHM1 and CALHM3. First, I discovered protein palmitoylation on CALHM1 regulating its gating and localization. Second, I identified a CALHM1/3 heteromer as the neurotransmitter-release pathway in taste receptor cells of the taste buds required for taste perception. Third, I elucidated the structure and localization of CALHM channel synapses in taste cells. Lastly, my analyses uncovered sensory cells expressing CALHM channel subunits.
These findings revealed the structure, localization, molecular mechanisms, function, and regulatory mechanisms of CALHM channel synapses of the taste buds, and further proposed novel physiological function of CALHM synapses.

Academic Significance and Societal Importance of the Research Achievements

細胞外ATPシグナルは味覚・機械・侵害など多くの感覚情報伝達など幅広い生理現象を担うが、多くの場合細胞からのATP放出の分子機構は不明である。本研究では味覚の認識を担う味蕾細胞からの神経伝達物質ATPの放出経路としてCALHM1/3チャネルを同定し、その機能調節機構も発見した。さらに、CALHMチャネルが担う味蕾細胞シナプスの構造とその形成原理の一端を明らかにすることで、シナプス小胞を持たない”イオンチャネルシナプス”とも呼ぶべき全く新しい化学シナプスの概念を確立した。さらにCALHMチャネルシナプスの新たな機能部位を示唆するデータを得たことは新たな学術領域の萌芽である。

Research Products

• [Int'l Joint Research] ペンシルバニア大学/モネル化学感覚研究所/カリフォルニア大学アーバイン校(米国)
• [Int'l Joint Research] ペンシルバニア大学/モネル化学感覚研究所(米国)
• [Int'l Joint Research] コペンハーゲン大学(デンマーク)
• [Journal Article] CALHM1/CALHM3 channel is intrinsically sorted to the basolateral membrane of epithelial cells including taste cells (2019)
  • Author(s): Kashio M, Wei-Qi G, Ohsaki Y, Kido MA, Taruno A
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 2681-2681
  • DOI: 10.1038/s41598-019-39593-5
  • Peer Reviewed / Open Access
• [Journal Article] AAV-Mediated Gene Delivery to Taste Cells of the Tongue (2019)
  • Author(s): Taruno A and Kashio M
  • Journal Title: Methods in Molecular Biology Volume: 1950 Pages: 299-307
  • DOI: 10.1007/978-1-4939-9139-6_18
  • ISBN: 9781493991389, 9781493991396
  • Peer Reviewed / Open Access
• [Journal Article] CALHM3 Is Essential for Rapid Ion Channel-Mediated Purinergic Neurotransmission of GPCR-Mediated Tastes (2018)
  • Author(s): Ma Zhongming、Taruno Akiyuki、Ohmoto Makoto、Jyotaki Masafumi、Lim Jason C.、Miyazaki Hiroaki、Niisato Naomi、Marunaka Yoshinori、Lee Robert J.、Hoff Henry、Payne Riley、Demuro Angelo、Parker Ian、Mitchell Claire H.、Henao-Mejia Jorge、Tanis Jessica E.、Matsumoto Ichiro、Tordoff Michael G.、Foskett J. Kevin
  • Journal Title: Neuron Volume: 98 Issue: 3 Pages: 30249-30256
  • DOI: 10.1016/j.neuron.2018.03.043
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Innate and acquired tolerance to bitter stimuli in mice (2018)
  • Author(s): Mura Emi、Taruno Akiyuki、Yagi Minako、Yokota Kohei、Hayashi Yukako
  • Journal Title: PLOS ONE Volume: 13 Issue: 12 Pages: e0210032-e0210032
  • DOI: 10.1371/journal.pone.0210032
  • Peer Reviewed / Open Access
• [Journal Article] Action of Protein Tyrosine Kinase Inhibitors on the Hypotonicity-Stimulated Trafficking Kinetics of Epithelial Na⁺ Channels (ENaC) in Renal Epithelial Cells: Analysis Using a Mathematical Model (2018)
  • Author(s): Marunaka Rie、Taruno Akiyuki、Yamamoto Toshiro、Kanamura Narisato、Marunaka Yoshinori
  • Journal Title: Cellular Physiology and Biochemistry Volume: 50 Issue: 1 Pages: 363-377
  • DOI: 10.1159/000494012
  • Peer Reviewed / Open Access
• [Journal Article] 塩味の受容とそのメカニズムについて (2018)
  • Author(s): 樽野陽幸
  • Journal Title: 日本味と匂学会誌 Volume: 25 Pages: 79-82
• [Journal Article] ATP Release Channels (2018)
  • Author(s): Taruno Akiyuki
  • Journal Title: International Journal of Molecular Sciences Volume: 19 Issue: 3 Pages: 808-808
  • DOI: 10.3390/ijms19030808
  • Peer Reviewed / Open Access
• [Journal Article] The NOX1 isoform of NADPH oxidase is involved in dysfunction of liver sinusoids in nonalcoholic fatty liver disease. (2018)
  • Author(s): Matsumoto M, Zhang J, Zhang X, Liu J, Jiang JX, Yamaguchi K, Taruno A, Katsuyama M, Iwata K, Ibi M, Cui W, Matsuno K, Marunaka Y, Itoh Y, Torok NJ, Yabe-Nishimura C.
  • Journal Title: Free Radic Biol Med. Volume: 115 Pages: 412-420
  • DOI: 10.1016/j.freeradbiomed.2017.12.019
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Post-translational palmitoylation controls the voltage gating and lipid raft association of the CALHM1 channel. (2017)
  • Author(s): Taruno A, Sun H, Nakajo K, Murakami T, Ohsaki Y, Kido MA, Ono F, Marunaka Y.
  • Journal Title: Journal of Physiology Volume: 595 Issue: 18 Pages: 6121-6145
  • DOI: 10.1113/jp274164
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Current-direction/amplitude-dependent single channel gating kinetics of mouse pannexin 1 channel: a new concept for gating kinetics (2017)
  • Author(s): Nomura Takeshi、Taruno Akiyuki、Shiraishi Makoto、Nakahari Takashi、Inui Toshio、Sokabe Masahiro、Eaton Douglas C.、Marunaka Yoshinori
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 10512-10512
  • DOI: 10.1038/s41598-017-10921-x
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 甘味受容の仕組みと人工甘味料 (2017)
  • Author(s): 樽野陽幸
  • Journal Title: 食と医療 Volume: 2 Pages: 40-46
• [Journal Article] Adeno-Associated Virus-Mediated Gene Transferinto Taste Cells In Vivo (2017)
  • Author(s): Taruno A, Kashio M, Sun H, Kobayashi K, Sano H, Nambu A, Marunaka Y
  • Journal Title: Chemical Senses Volume: 42 Pages: 69-78
  • DOI: 10.1093/chemse/bjw101
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Hypotonicity activates a voltage-dependent membrane conductance in N2a neuroblastoma cells. (2017)
  • Author(s): Taruno, A. & Marunaka, Y.
  • Journal Title: Biochem Biophys Res Commun Volume: 482 Issue: 2 Pages: 331-335
  • DOI: 10.1016/j.bbrc.2017.01.118
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Analysis of aprotinin, a protease inhibitor, action on the trafficking of epithelial Na+ channels (ENaC) in renal epithelial cells using a mathematical model. (2017)
  • Author(s): Sasamoto, K., Marunaka, R. #, Niisato, N., Sun, H., Taruno, A., Pezzotti, G., Yamamoto, T., Kanamura, N., Zhu, W., Nishio, K., Inui, T., Eaton, D.C., & Marunaka, Y.
  • Journal Title: Cell Physiol Biochem Volume: 41 Issue: 5 Pages: 1865-1880
  • DOI: 10.1159/000471934
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Actions of quercetin, a polyphenol, on blood pressure. (2017)
  • Author(s): Marunaka, Y., Marunaka, R., Sun, H., Yamamoto, T., Kanamura, N., Inui, T. & Taruno, A.
  • Journal Title: Molecules Volume: 22 Issue: 2 Pages: 209-209
  • DOI: 10.3390/molecules22020209
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Ion channel synapses of the taste bud (2019)
  • Author(s): Taruno A, Ma Z, Ohmoto M, Matsumoto I, Kido MA, Tordoff MG, Foskett JK
  • Organizer: The 9th Federation of the Asian and Oceanian Physiological Societies (FAOPS) Congress (in conjunction with the 96th Annual Meeting of the Physiological Society of Japan)
  • Int'l Joint Research
• [Presentation] Taste cells lacking synapses open a wide pore channel for rapid neurotransmission of tastes (2018)
  • Author(s): Taruno A
  • Organizer: 第56回日本生物物理学会大会
• [Presentation] Ion channel synapse: CALHM1/3 channel mediates rapid neurotransmitter release in taste perception (2018)
  • Author(s): Taruno A
  • Organizer: 第41回日本神経科学大会
• [Presentation] 塩味の受容とそのメカニズムについて (2018)
  • Author(s): 樽野陽幸
  • Organizer: うま味研究会公開シンポジウム
  • Invited
• [Presentation] CALHMs: Fast-activating voltage-gated ATP channels for rapid purinergic neurotransmission (2018)
  • Author(s): Taruno A, Ma Z, Ohmoto M, Matsumoto I, Kido MA, Tordoff MG, Foskett JK
  • Organizer: The 49th National Institute of Physiological Sciences International Symposium “Ion channels: looking back, seeing ahead”
  • Int'l Joint Research / Invited
• [Presentation] Ion channel synapses of the taste bud (2018)
  • Author(s): Taruno A, Ma Z, Ohmoto M, Matsumoto I, Kido MA, Tordoff MG, Foskett JK
  • Organizer: The 17th International Symposium on Molecular and Neural Mechanisms of Taste and Olfactory Perception
  • Int'l Joint Research / Invited
• [Presentation] Ion channel synapses in taste buds (2018)
  • Author(s): Taruno A, Ma Z, Ohmoto M, Matsumoto I, Tordoff MG, Foskett JK
  • Organizer: 第52回日本味と匂学会大会
• [Presentation] イオンチャネルから味覚へ（研究奨励賞受賞講演） (2018)
  • Author(s): 樽野陽幸
  • Organizer: 第52回日本味と匂学会大会
• [Presentation] A CALHM1/CALHM3 heteromeric channel mediates purinergic neurotransmission of sweet, bitter, and umami tastes. (2018)
  • Author(s): Taruno A, Zhongming M, Ohmoto M, Matsumoto I, Tordoff MG, Foskett JK, Marunaka Y.
  • Organizer: 第95回日本生理学会大会
• [Presentation] Neurotransmission of taste mediated by calcium homeostasis modulator ion channels. (2017)
  • Author(s): 樽野陽幸, 丸中良典
  • Organizer: 第94回日本生理学会大会.
  • Place of Presentation: 浜松（アクトシティ浜松）
  • Year and Date: 2017-03-28
• [Presentation] Palmitoylation regulates gating and lipid raft association of CALHM1 channel. (2017)
  • Author(s): 孫紅キン, 樽野陽幸, 中條浩一, 小野富三人, 丸中良典
  • Organizer: 第94回日本生理学会大会.
  • Place of Presentation: 浜松（アクトシティ浜松）
  • Year and Date: 2017-03-28
• [Presentation] Molecular basis of polarized sorting of CALHM channels in epithelial cells. (2017)
  • Author(s): 加塩麻紀子, 樽野陽幸, 丸中良典
  • Organizer: 第94回日本生理学会大会.
  • Place of Presentation: 浜松（アクトシティ浜松）
  • Year and Date: 2017-03-28
• [Presentation] Current-direction/amplitude-dependent single channel gating kinetics of Pannexin 1 channel. (2017)
  • Author(s): 白石真土, 野村健, 樽野陽幸, 丸中良典
  • Organizer: 第94回日本生理学会大会.
  • Place of Presentation: 浜松（アクトシティ浜松）
  • Year and Date: 2017-03-28
• [Presentation] CALHM channel-mediated neurotransmission of tastes. (2017)
  • Author(s): Taruno A
  • Organizer: The 19th Scientific Meeting of the Australasian Association for ChemoSensory Science
  • Int'l Joint Research
• [Presentation] Palmitoylation of CALHM3 positively controls activity of the CALHM1/3 channel. (2017)
  • Author(s): 奥井元貴, 孫紅昕, 樽野陽幸, 丸中良典
  • Organizer: 第110回近畿生理学談話会
• [Presentation] パルミトイル化がCALHM1チャネルのゲーティングと脂質ラフト局在を制御する (2017)
  • Author(s): 樽野陽幸、孫 紅昕 、中條浩一、村上達郎、大崎康吉、城戸瑞穂、小野富三人、丸中良典
  • Organizer: 日本味と匂学会第51回大会
• [Presentation] Induction of foreign genes in taste cells in vivo. (2016)
  • Author(s): Taruno, A.
  • Organizer: The 15th international symposium on molecular and neural mechanisms of taste and olfactory perception.
  • Place of Presentation: 福岡（九州大学）
  • Year and Date: 2016-12-03
  • Int'l Joint Research
• [Presentation] Molecular machinery for taste neurotransmission from the tongue to the brain. (2016)
  • Author(s): Taruno, A.
  • Organizer: the 2nd UK-Japan Frontiers of Science Symposium.
  • Place of Presentation: UK
  • Year and Date: 2016-11-07
  • Int'l Joint Research
• [Presentation] Homologous CALHM subunits assemble to form a novel voltage-gated ATP channel. (2016)
  • Author(s): Taruno A, Miyazaki H, Niisato N, Sun H, Kashio M, Marunaka Y.
  • Organizer: 第39回日本神経科学会大会.
  • Place of Presentation: 横浜（パシフィコ横浜）
  • Year and Date: 2016-07-20
• [Presentation] Purinergic neurotransmission of taste by CALHM channel. (2016)
  • Author(s): Taruno A, Marunaka Y.
  • Organizer: 17th International Symposium on Olfaction and Taste.
  • Place of Presentation: 横浜（パシフィコ横浜）
  • Year and Date: 2016-06-05
  • Int'l Joint Research
• [Presentation] Regulation of CALHM1 channel by protein S-palmitoylation. (2016)
  • Author(s): Taruno A, Hongxin Sun, Makiko Kashio, Marunaka Y.
  • Organizer: 17th International Symposium on Olfaction and Taste.
  • Place of Presentation: 横浜（パシフィコ横浜）
  • Year and Date: 2016-06-05
  • Int'l Joint Research
• [Presentation] S－パルミトイル化修飾によるCALHM1チャネル機能制御. (2016)
  • Author(s): Taruno A, Sun H, Kashio M, Marunaka Y.
  • Organizer: 日本膜学会第３９年会.
  • Place of Presentation: 東京（早稲田大学）
  • Year and Date: 2016-05-10
• [Book] 摂食と健康の科学 (2019)
  • Author(s): 樽野陽幸
  • Total Pages: 240
  • Publisher: 朝倉書店
• [Remarks] 樽野研究室ホームページ
  • URL: https://www.tarunolab.com
• [Remarks] 京都府立医科大学細胞生理学website
  • URL: http://kpum-molecular-cell-physiology.info