Animal cell behavior is tightly linked to mechanical stresses produced by the environment and mechanochemistry illustrated most vividly by muscle contraction and hearing. There is an enormous amount of physiology and disease connected to forces and sensing including hemodynamics, coordinated movement, touch, cardiac arrhythmias, muscular dystrophy, edema, glaucoma, deafness, high blood pressure, etc. The cell cortex forms the interface between the environment and the cell and this project addresses the distribution of stress in the cell cortex and how it is sensed by mechanosensitive ion channels (MSCs). We will analyze how stress is shared by specific cytoskeletal proteins, the lipid bilayer, and sensed by mechanosensitive ion channels. The project has two specific aims directed at patches and whole cells and creating a basis for extrapolating from high resolution patch data to cell behavior. The patch experiments will localize different channels and cytoskeletal proteins within the patch;measure stress in cytoskeletal proteins as the patch is stressed;create patches with minimal cytoskeleton to simplify the stress distribution;measure and quantify endogenous and TREK-1 channel kinetics in terms of membrane tension;characterize the properties of microdomains within the patch using channel kinetics, patch capacitance, fluorescence imaging of labeled proteins and the stress in specific labeled cytoskeletal proteins. The whole cell experiments will use a combination of scanning conductance microscopy (SICM), whole cell patch clamp and fluorescent probes to examine the distribution of cytoskeletal proteins and channels and the stress in cytoskeletal proteins as the cell are stressed by the SICM. We will use MSCs calibrated in the patch as additional probes of bilayer stress.

Public Health Relevance

Mechanical forces in biology account for hearing, muscle contraction, blood pressure regulation and a great deal more. As expected for such ubiquitous processes, they are also involved in much pathology such as cardiac arrhythmias, high blood pressure and muscular dystrophy. This proposal analyses how stresses are distributed in molecules, membranes and cells and how that leads to signal transduction by ion channels.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MDCN-C (02))
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Krull, Holly
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State University of New York at Buffalo
Schools of Medicine
United States
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Bae, Chilman; Suchyna, Thomas M; Ziegler, Lynn et al. (2016) Human PIEZO1 Ion Channel Functions as a Split Protein. PLoS One 11:e0151289
Cox, Charles D; Bae, Chilman; Ziegler, Lynn et al. (2016) Removal of the mechanoprotective influence of the cytoskeleton reveals PIEZO1 is gated by bilayer tension. Nat Commun 7:10366
Peng, Anthony W; Gnanasambandam, Radhakrishnan; Sachs, Frederick et al. (2016) Adaptation Independent Modulation of Auditory Hair Cell Mechanotransduction Channel Open Probability Implicates a Role for the Lipid Bilayer. J Neurosci 36:2945-56
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Nishizawa, Kazuhisa; Nishizawa, Manami; Gnanasambandam, Radhakrishnan et al. (2015) Effects of Lys to Glu mutations in GsMTx4 on membrane binding, peptide orientation, and self-association propensity, as analyzed by molecular dynamics simulations. Biochim Biophys Acta 1848:2767-78
Bae, Chilman; Sachs, Frederick; Gottlieb, Philip A (2015) Protonation of the human PIEZO1 ion channel stabilizes inactivation. J Biol Chem 290:5167-73

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