Periodic Reporting for period 4 - SENSATIONAL TETHERS (Tethers for sensory mechanotransduction: from molecules to perception)
Okres sprawozdawczy: 2023-01-01 do 2024-06-30
Touch sensation is built upon the ability of sensory neurons to detect and transduce nanometer scale mechanical displacements. The underlying process has been termed mechanotransduction: the high sensitivity and speed of which is enabled by direct gating (opening) of ion channels by mechanical force. Force detection is functionally compartmentalized and only takes place at the peripheral endings of sensory neurons in vivo. Now three molecules were found to be genetically necessary for touch in many sensory neurons, the force gated ion channel PIEZO2 and its modulator STOML3 and the mechanically gated ion channel ELKIN1. However, mechanotransduction complexes in all touch receptors absolutely require tethering to the extracellular matrix for function. Tethering is dependent on large extracellular proteins that are sensitive to site-specific proteases. Here we have for the first time identified the first molecular component of these tethers, a protein called TENM4. To do this we developed technology to acutely and reversibly abolish tethers and other mechanotransducer components. We have used genome engineering to tag tethers and mechanotranduction components in order to visualize and manipulate these proteins at their in vivo sites of action. By engineering de novo cleavage sites for site-specific proteases we rendered tethers newly sensitive to normally ineffective proteases in the skin. We have also now generated mutations into candidate ion channels that dramatically alter biophysical properties to physiologically “mark” function in vivo. Furthermore, the impact of acute and reversible manipulation of mechanotransduction on touch perception has been measured. Our results provide the basis of novel translational efforts to develop drugs to modulate pathological touch as well as pain.
Tether proteins and the ion channel that are opened by mechanical force are necessary for touch sensation. In this project we used a molecular approach to identify the molecular nature of tether proteins that are directly involved in the transduction of touch. We used molecular approaches to screen for candidates and then generated a series of mouse models in which the function of these candidates could be directly manipulated. Using this approach, we identified the proteins USHS2A, TENM4 and ELKIN1 ion channels as essential and novel components of touch transduction. In addition, we identified an unexpected role for PIEZO2 channels in the sensitization fof pain receptors in mice. All these results have been ,or are in the process of being disseminated in the form of scientifioc publications. The results have significant translational potential for the development of novel pain therapies. The PI is following up these avenues in his lab and potentially in collaboration with industry.
By identifying novel and crucial molecules for touch and pain the project has achieved results that go significantly beyond state of the art. We found for example that TENM4 is not only essential for touch but also for fast pain transduction. Additionally we identified a new ion channel for touch, ELKIN1, which is also potentially important therapeutic target for pain. Understanding how molecules assemble to function in a mechanotransduction complex in the skin will open up avenues to develop therapeutic strategies to modulate touch. The project will be followed up with translational approaches to identify small molecules that could be developed into novel analgesics and industry collaborations have been initiated.