Lou Beaulieu-Laroche, Marine Christin, Annmarie Donoghue, Francina Agosti, Noosha Yousefpour, Hugues Petitjean, Albena Davidova, Craig Stanton, Uzair Khan, Connor Dietz, Elise Faure, Tarheen Fatima, Amanda MacPherson, Stephanie Mouchbahani-Constance, Daniel G. Bisson, Lisbet Haglund, Jean A. Ouellet, Laura S. Stone, Jonathan Samson, Mary-Jo Smith, Kjetil Ask, Alfredo Ribeiro-da-Silva, Rikard Blunck, Kate Poole, Emmanuel Bourinet, and Reza Sharif-Naeini TACAN is an ion channel involved in sensing mechanical pain. Cell. Volume 180 issue 5. Page 956-967. https://www.cell.com/cell/pdf/S0092-8674(20)30114-8.pdf
Identification of TACAN as a novel mechanical pain sensor and target for pain therapies
Our understanding of pain sensing has been hindered by a lack of knowledge concerning the key molecular players. Detecting mechanical stimuli is essential for physiological functions such as touch, hearing, and proprioception. It involves sensor proteins that convert mechanical forces into electrical signals that can be relayed to the brain. Although several mechanical sensors have been identified, the sensors for our most unwanted experience, pain, remain elusive. In this paper, Lou Beaulieu-Laroche and collaborators report the identification of TACAN, a novel mechanical sensor implicated in pain sensing.
The researchers identified TACAN as a protein located in the cell membrane that had the ability to robustly increase the magnitude of mechanically-evoked electrical signals in cells. They confirmed it acted as a mechanical sensor by purifying and reconstituting TACAN in synthetic lipids. Next, they tested the role of TACAN in nociceptors, which are pain sensing neurons that innervate the skin. They found that mechanically-evoked electrical signals were drastically decreased in nociceptors with reduced TACAN expression. This suggested that TACAN endowed nociceptors with mechanical sensitivity, but did not determine if it was necessary to detect painful mechanical stimuli. To address this, the researchers genetically removed TACAN from nociceptors in mice, which resulted in an impaired ability to detect painful mechanical stimuli.
Through these experiments TACAN was identified as a protein essential for the detection of painful mechanical stimuli in nociceptors and for sensing mechanical pain in mice. Because it is a conserved protein across mice and humans, they expect TACAN to be key to detecting painful mechanical events such as stubbing a toe.
The identification of TACAN provides a new molecular handle to dissect pain sensation. It will now be possible to genetically target TACAN to disrupt pain circuits and enhance our understanding of pain physiology. This discovery also opens the way to better understand other mechanical processes such as hearing and proprioception. They found that TACAN is expressed in many different organs and tissues and likely to play key biological roles in addition to pain sensing.
In addition to advancing our understanding of pain or other mechanical processes, these findings have crucial implications for developing therapies for pain disorders. While for most, mechanical pain is a transient and arguably necessary experience, this is not the case for people with chronic pain. Patients with conditions such as osteoarthritis, rheumatoid arthritis, or neuropathic pain often develop mechanical allodynia, a condition where pain signals are elicited without external triggers. The lack of molecular targets has plagued the development of effective pain therapies. TACAN is now an extremely valuable target as the molecular sensor of mechanical pain. This publication paves the way to develop new pain therapies to suppress pain signaling at its source and brings hope for novel pain treatment.
As an undergraduate researcher at McGill University, Lou Beaulieu-Laroche worked in the laboratory full time for a year as part of an honors research project and an NSERC Undergraduate Student Research Awards (August 2014-August 2015). Despite being an undergraduate with limited research experience, he overcame a steep learning curve to take the lead in a project with 26 scientists. He conceived the study and wrote the article together with Reza Sharif-Naeini, his supervisor at the time and last author on the article.
This work was supported by the Canadian Institutes of Health Research, the Groupe d’Etude des Protéines Membranaires (GEPROM), and the Fonds de Recherche du Quebec-Santé. Collaborators were supported by Fondation pour la Recherche Médicale, Agence Nationale pour la Recherche, NHMRC, the Louise and Alan Edwards Foundation, Natural Sciences and Engineering Research Council of Canada, the Ontario Thoracic Society and the Canada Foundation for Innovation John R. Evans Leaders Fund.