Sensory biology research has been transformed in recent years with the cloning of molecules that mediate the conversion of sensory stimuli into biological signals. The understanding of taste, smell, and temperature sensation is now approaching that of the visual system reached long ago. Mechanotransduction is perhaps the last sensory modality to be understood at the molecular level. Cation channels that sense mechanical force are postulated to play critical roles in sensing touch/pain (somatosensation), sound (hearing), sheer stress (cardiovascular function), stretch (lung growth and function), and basic cellular processes such as cell division and migration. However, the identity of such ion channels has remained elusive.
A few excitatory mechanically activated (MA) ion channels have been identified in bacteria and invertebrates but none in vertebrates. We have recently applied bioinformatic and genomic approaches to identifying molecules involved in mechanotransduction. In our first project in this area, we employed small interfering RNA knockdown of MA currents in mouse Neuro2A cells to screen candidate channels. We found that knockdown of Fam38A (family with sequence similarity #38) caused a pronounced decrease of MA currents. Importantly, we showed that overexpression of this gene in heterologous cells gave rise to large MA currents. We renamed the gene Piezo1. In collaboration with Mauricio Montal's lab (University of California, San Diego), we have since shown that Piezo1 and the related Piezo2 are bona fide ion channels. Working with Boaz Cook (Scripps Research Institute), we have also found that Drosophila piezo plays an essential role in sensing noxious mechanical forces. dPiezo was the first ion channel shown to be sufficient to induce MA currents when expressed in heterologous cells and to be required for mechanotransduction in vivo. Interestingly, we and others have shown that gain-of-function mutations in Piezo1 and Piezo2 in humans cause hereditary xerocytosis and arthrogryposis, respectively.
Because molecular identification of sensory receptors has led to a fundamental understanding of other senses, we expect that an in-depth investigation of Piezo proteins will break open the field of mechanotransduction. This ambitious research program will require a challenging breadth of experiments across multiple specialties of biology. Furthermore, identifying Piezos has provided proof of concept for our strategy for finding novel ion channels, and we are developing innovative screens in pursuit of this aim.
Our goal is to synthesize a thorough molecular understanding of mechanosensation. In the next few years, we will focus on understanding structure-function relationships of Piezo proteins and elucidating their physiological roles in biological processes and diseases that involve mechanotransduction. We are also searching for novel ion channels and other receptors involved in thermosensation and mechanosensation. In the long term, we will seek a deeper understanding of mechanosensation. Sensing force is crucial for development, physiology, and disease, yet we have very little mechanistic understanding of this process. With Piezos and potentially other sensors serving as a critical foothold, we will explore how mechanical information is sensed and transmitted and what signaling pathways are involved. We wish to develop a combined cell biological, biophysical, and genetic interdisciplinary approach to address mechanotransduction, arguably the most important remaining question in vertebrate sensory transduction. We hope that our wide-ranging studies will lead to a fundamental description of mechanosensation and contribute to novel approaches to treating various diseases that involve mechanotransduction.
Grants from the National Institutes of Health provided partial support for some of these projects.
As of February 19, 2016