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Cells throughout the human body detect mechanical forces. While it is known that the rapid (millisecond) detection of mechanical forces is mediated by force-gated ion channels, technological limitations have precluded a detailed quantitative understanding of cells as sensors of mechanical energy. Here, I describe the development and validation of a system combining atomic force microscopy with patch-clamp electrophysiology. Using this system, I develop a quantitative framework for describing cells as sensors of mechanical energy and determine the physical limits of detection and resolution of mechanical energy for cells expressing the force-gated ion channels Piezo1, Piezo2, TREK1, and TRAAK. I find that, depending on the identity of the channel, cells can function either as proportional or nonlinear transducers of mechanical energy, detect mechanical energies as little as ~70 fJ, and with a resolution of up to ~1 fJ. I also make the surprising discovery that cells can transduce forces either nearly instantaneously (< 1ms), or with substantial time delay (~10 ms) dependent on the identity of the channel. Using a chimeric experimental approach and simulations we show how such delays can emerge from channel-intrinsic properties and the slow diffusion of tension in cellular membranes. Further, I explore the role that cellular properties such as cell size, channel density, and actin cytoarchitecture play in tuning the biophysical limits of rapid cellular mechanotransduction. Overall, our experiments reveal the capabilities and limits of cellular mechanosensing and provide insights into molecular mechanisms that different cell types may employ to specialize for their distinct physiological roles.
Neurobiology Dissertation Seminar