Pain is a warning signal of an organism, generally detected by nociceptors and signaled by the opening of mechanical force sensitive channels, such as the Piezo mechanical force channel, which not only conducts the sense of touch, but is also related to the mechanical force caused pain (1). In March 2020, Canadian scientists discovered a new ion channel, named TACAN, that can sense acute mechanical pain in daily life (2), such as the pain caused by a hammer hitting a finger. In May 2021, US scientists further utilized rat models to find that TACAN plays a role in pain generated by inflammation, but not in chemotherapy-induced pain (3). However, in August 2021 in the same issue of Elife, the research group of Roderick Mackinnon, a 2003 Nobel laureate at Rockefeller University (4), the Youxing Jiang research group of the Southwest Research Center in Texas (5), the research group of Liu Zhenfeng / Zhao Yan research group / Xiao Bailong research group of Tsinghua University / the Institute of Biophysics, the Chinese Academy of Sciences published three articles back-to-back (6), they independently analyzed the cryo-EM structure of TACAN, respectively. It was unanimously proposed that TACAN may be a coenzyme A-binding protein rather than a mechanically sensitive ion channel. Subsequently, Yan Zhen's research group at Westlake University analyzed the cryo-EM structure of different isomers of TACAN, and published an article in the journal of Cell Discovery, suggesting that the biological function of TACAN may be an enzyme in the process of lipid metabolism (7). These three-dimensional structures challenge the biological function of TACAN as an ion channel, but also fail to provide strong evidence to determine the true biological function of TACAN.

On March 1, 2022, Shen Yuequan/Yang Xue team of Nankai University published an article entitled Cryo-EM structure of the human TACAN channel in a closed state in Cell Reports, which used cryo-EM technology to analyze the three-dimensional structure of TACAN protein in a resting state. Combining electrophysiological experiments and molecular dynamics simulations, the ion conduction path of TACAN protein and the possible mechanical gating mechanism were determined.

Figure 1 Cryo-EM structure of TACAN protein

Analyzing the cryo-EM structure of TACAN, the team found great similarities between the assembly of TACAN and OSCA (Hyperosmolality-gated calcium-permeable channel), another mechanical force-sensitive channel. Molecular dynamics simulation of TACAN found that in the resting state, water molecules could not form continuous pathways on the inside and outside of the protein, indicating that TACAN was closed at this time. When the tension force of the phospholipid bilayer applied in the molecular dynamics simulation system reaches 35 mN/m, water molecules pass through the middle pore of the TACAN monomer, forming a continuous pathway on the inside and outside of the phospholipid bilayer. Among them, the amino acids M207, F223 and N165 three amino acid residues constitute the restriction region of the pores. Measuring the current by electrophysiological technology showed that the amplitude of the current change of wild-type TACAN was not obvious in response to membrane tension. However, the current of the gated amino acid M207 mutant increased by nearly a sixfold factor in response to membrane tension. Therefore, the team believes that the TACAN protein is in a closed state at rest (which is similar to the results published by other research groups), and other unknown cofactors may be needed to help the channel transition to another state (such as a pre-activated state), which can be further converted to an open state after sensing mechanical forces. The mechanism of this double locking is consistent with the biological function of TACAN channels in sensing acute mechanical pain.

The team's current findings support TACAN as a new type of mechanically sensitive ion channel. It is foreseeable that more data will be available in the future to further determine the exact biological function of TACAN, and more and broader scientific debates will be of great significance for the discovery of novel mechanically sensitive ion channels and the development of new non-addictive painkillers.

Figure 2 Possible activation mechanisms of TACAN protein.

Professor Shen Yuequan and Professor Yang Xue from the State Key Laboratory of Medicinal Chemical Biology, School of Life Sciences, Nankai University, are the co-corresponding authors of this paper, and Chen Xiaozhe, Wang Yaojie, and postdoctoral fellow Li Yang of the School of Life Sciences of Nankai University are the co-first authors of this paper. The cryo-EM data was collected from the cryo-EM center of Zhejiang University.

Link: https://www.cell.com/cell-reports/fulltext/S2211-1247(22)00172-3

References:

1.       Murthy, S. E., Dubin, A. E., and Patapoutian, A. (2017) Piezos thrive under pressure: mechanically activated ion channels in health and disease. Nat Rev Mol Cell Biol 18, 771-783

2.       Beaulieu-Laroche, L., Christin, M., Donoghue, A., Agosti, F., Yousefpour, N., Petitjean, H., Davidova, A., Stanton, C., Khan, U., Dietz, C., Faure, E., Fatima, T., MacPherson, A., Mouchbahani-Constance, S., Bisson, D. G., Haglund, L., Ouellet, J. A., Stone, L. S., Samson, J., Smith, M. J., Ask, K., Ribeiro-da-Silva, A., Blunck, R., Poole, K., Bourinet, E., and Sharif-Naeini, R. (2020) TACAN Is an Ion Channel Involved in Sensing Mechanical Pain. Cell 180, 956-967

3.       Bonet, I. J. M., Araldi, D., Bogen, O., and Levine, J. D. (2021) Involvement of TACAN, a Mechanotransducing Ion Channel, in Inflammatory But Not Neuropathic Hyperalgesia in the Rat. J Pain 22, 498-508

4.       Niu, Y., Tao, X., Vaisey, G., Olinares, P. D. B., Alwaseem, H., Chait, B. T., and MacKinnon, R. (2021) Analysis of the mechanosensor channel functionality of TACAN. Elife 10, e71188

5.       Xue, J., Han, Y., Baniasadi, H., Zeng, W., Pei, J., Grishin, N. V., Wang, J., Tu, B. P., and Jiang, Y. (2021) TMEM120A is a coenzyme A-binding membrane protein with structural similarities to ELOVL fatty acid elongase. Elife 10, e71220

6.       Rong, Y., Jiang, J., Gao, Y., Guo, J., Song, D., Liu, W., Zhang, M., Zhao, Y., Xiao, B., and Liu, Z. (2021) TMEM120A contains a specific coenzyme A-binding site and might not mediate poking- or stretch-induced channel activities in cells. Elife 10, e71474

7.       Ke, M., Yu, Y., Zhao, C., Lai, S., Su, Q., Yuan, W., Yang, L., Deng, D., Wu, K., Zeng, W., Geng, J., Wu, J., and Yan, Z. (2021) Cryo-EM structures of human TMEM120A and TMEM120B. Cell Discov 7, 77