Mechanosensitive ion channels are essential for mechanotransduction, or the conversion of mechanical force into a biologically relevant signal. Recently, two novel membrane-spanning proteins, Piezo1 and Piezo2, were identified as pore-forming subunits of a vertebrate mechanosensitive ion channel. Piezos open in response to diverse mechanical stimuli, leading to an influx of cations; this in turn leads to depolarization o the cell membrane and initiation of downstream pathways. Piezos are required for responses to light touch in Merkel cells and normal development of the vascular system. Moreover, disruption of Piezo ion channel function is implicated in several human diseases and may contribute to hyperalgesia associated with inflammatory pathways. Piezos share little homology with other ion channels, and despite their important role in normal physiology many aspects of their function remain unknown. In particular, the specific forces on the membrane and/or channel that lead to pore opening have yet to be established. The experiments proposed here are designed to elucidate the activation mechanism of Piezos. Specifically, they test the contributions of membrane curvature and/or tension as potential physical stimuli that Piezos sense. Additionally, these experiments will examine the mechanisms by which inflammatory compounds as well as native inactivation modulate the sensitivity of Piezos to a given stimulus. Identifying the physica stimulus that activates Piezos and the means by which it can be modulated will help further the understanding of the role of these proteins in abnormal physiology, as well as inform pharmacological targeting.
The ability to sense mechanical force and convert it into biological signals (mechanotransduction) is essential for many physiological processes, including the sensation of touch and pain, embryonic development, and regulation of blood flow. Piezos are recently discovered mechanosensitive ion channels that initiate mechanotransduction by opening in response to mechanical stimuli and permitting the flow of cations that lead to downstream signaling. The goal of the experiments proposed here is to define the precise forces that Piezos sense, in hopes of further understanding the contribution of Piezos to human disease.
| Lewis, Amanda H; Grandl, Jörg (2018) A cellular mechanism for age-induced itch. Science 360:492-493 |
| Dubin, Adrienne E; Murthy, Swetha; Lewis, Amanda H et al. (2017) Endogenous Piezo1 Can Confound Mechanically Activated Channel Identification and Characterization. Neuron 94:266-270.e3 |
| Wu, Jason; Young, Michael; Lewis, Amanda H et al. (2017) Inactivation of Mechanically Activated Piezo1 Ion Channels Is Determined by the C-Terminal Extracellular Domain and the Inner Pore Helix. Cell Rep 21:2357-2366 |
| Lewis, Amanda H; Cui, Alisa F; McDonald, Malcolm F et al. (2017) Transduction of Repetitive Mechanical Stimuli by Piezo1 and Piezo2 Ion Channels. Cell Rep 19:2572-2585 |
| Wu, Jason; Lewis, Amanda H; Grandl, Jörg (2017) Touch, Tension, and Transduction - The Function and Regulation of Piezo Ion Channels. Trends Biochem Sci 42:57-71 |
| Lewis, Amanda H; Grandl, Jörg (2015) Mechanical sensitivity of Piezo1 ion channels can be tuned by cellular membrane tension. Elife 4: |
