Cell . . . How is the pain perceived?

Mechanical transmission refers to the process of converting mechanical force stimulation into electrochemical signals, which eventually leads to cell reaction.we are familiar with many physiological functions, such as touch, hearing, pain, proprioception and so on, which depend on mechanical transmission.we can find that the occurrence of these physiological processes is often at the millisecond or even subtle level, which indicates that the mechanical gate channels (MSCs) on the cell membrane are the key to the perception and transmission of these mechanical stimuli.in the past 10 years, researchers have found a series of MSCs that sense different mechanical stimuli, which makes us more clear about the molecular mechanism of mechanical force transmission. For example, piezo protein can sense and transmit tactile signals [1], while TMC1 and tmc2 are found to be auditory receptors [2].however, how are unpleasant feelings, such as pain, perceived? On February 20, 2020, Professor Reza Sharif naeini from McGill University of Canada and his collaborators published a report on cell entitled TACAN is an ion channel involved in sensing mechanical Pain's research (this work was published on the preprint website biorxiv in June 2018) reported and named a previously unknown ion channel protein TACAN, which is a pain receptor.so, how did TACAN come from? It turns out that in a cell article in 2009, the author used proteomic screening method to find more than 70 membrane proteins that may be related to mechanical force transmission, and some of them have unknown functions [3]. The author named one of them as TACAN.TACAN is a six fold transmembrane protein. Its sequence is highly conserved in vertebrates and expressed in different tissues and organs, especially in dorsal root ganglia (DRGs).considering that DRGs play an important role in tactile and pain signal transduction, the authors speculate that TACAN may perceive pain.pain signal transmission depends on nociceptors, and immunofluorescence results show that TACAN and nociceptor markers (P2X3, ginip, ib4) have strong co localization, which indicates that TACAN does exist in nociceptors.next, how to prove that TACAN is a pain Sensing MSc? According to the summary of previous studies [4], it should meet the following eight conditions: (1) it should be expressed in mechanically sensitive cells; (2) it must be a membrane protein; (3) overexpression can enhance the mechanical sensitivity of cells; (4) it can be activated under the stimulation conditions similar to the activation of nociceptors; (5) it can respond quickly (< lt; 5ms); and it should be able to be expressed in the cells with mechanical sensitivity; (2) it must be a membrane protein; (3) it can enhance the mechanical sensitivity of cells; (4) it can be activated under; (6) The results showed that the decrease of the expression level would decrease the mechanical sensitivity of the cells; (7) ion channels could be formed in the synthetic lipid membranes and kept open under mechanical stimulation; (8) the mechanical force signal transduction defects would be caused by knockout in vivo. The experimental results show that TACAN satisfies seven of the above eight conditions.first of all, overexpression of TACAN can enhance cell adhesion and mechanical evoked currents induced by whole cell mechanical stimulation, while decreasing TACAN expression can weaken the mechanical sensitivity of nociceptors.in addition, the authors purified TACAN and combined it with synthetic lipid membrane, which proved that TACAN could play the role of channel protein in vitro and was antagonized by known MSc inhibitors.finally, conditional knockout of TACAN in mouse DRGs blocked the perception of painful mechanical stimulation, but did not affect the sensitivity to tactile and thermal stimuli.it should be noted here that although both tactile and pain are derived from mechanical stimuli, the authors found that the threshold of mechanical stimuli causing pain is much higher than that of tactile stimuli, so this is a process mediated by two completely different receptors.the only regret is that the author can not apply mechanical stimulation to the synthetic lipid membrane after insertion of TACAN, so it can not completely prove that TACAN has the ability to feel pain stimulation in vitro.to sum up, Professor Reza Sharif naeini found and named a possible pain receptor TACAN on the basis of previous research, and verified it through a series of biochemical methods.this discovery not only deepens our understanding of how the body perceives pain, but more importantly, it has a good clinical prospect: many chronic diseases, such as osteoarthritis and rheumatoid arthritis, are closely related to the pain signal transduction caused by mechanical stimulation, and TACAN undoubtedly provides a new target for the intervention of these diseases. 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