The long-term objective of this project is to understand how an ion channel called Piezo1 endows living cells with the ability to sense mechanical forces in their environment. This ability underlies a wide range of physiological processes that are essential to life, including the control of cell size and shape, the coalescence of cells into an organ system, and blood pressure control. The experiments are designed on the principle that to understand we must first see what Piezo1 looks like in its various forms. To this end the electron microscope will be used. We must also observe the functional properties of Piezo1 under conditions in which we understand every component present. Then, by comparing the functional properties, that is, how much the channel opens and closes under known quantities of applied force, with the structures, we can construct a physics-based model to explain the observable properties of Piezo1. Because we know that biology is complex, in a final stage of this project we aim to determine structures of Piezo1 in the cell membrane. There, we cannot yet know all the components that are present, but we hope to further understand how the more complex environment of the cell regulates the behavior of Piezo1.

Public Health Relevance

This project seeks to understand how the Piezo1 ion channels endow cells with the ability to sense mechanical forces in their environment. This ability underlies a wide range of physiological processes that are essential to life.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM043949-30
Application #
10115942
Study Section
Biochemistry and Biophysics of Membranes Study Section (BBM)
Program Officer
Nie, Zhongzhen
Project Start
1990-04-01
Project End
2024-11-30
Budget Start
2020-12-03
Budget End
2021-11-30
Support Year
30
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Rockefeller University
Department
Biology
Type
Graduate Schools
DUNS #
071037113
City
New York
State
NY
Country
United States
Zip Code
10065
Lee, Chia-Hsueh; MacKinnon, Roderick (2018) Activation mechanism of a human SK-calmodulin channel complex elucidated by cryo-EM structures. Science 360:508-513
Hite, Richard K; MacKinnon, Roderick (2017) Structural Titration of Slo2.2, a Na+-Dependent K+ Channel. Cell 168:390-399.e11
Wang, Weiwei; MacKinnon, Roderick (2017) Cryo-EM Structure of the Open Human Ether-à-go-go-Related K+ Channel hERG. Cell 169:422-430.e10
Lee, Chia-Hsueh; MacKinnon, Roderick (2017) Structures of the Human HCN1 Hyperpolarization-Activated Channel. Cell 168:111-120.e11
Tao, Xiao; Hite, Richard K; MacKinnon, Roderick (2017) Cryo-EM structure of the open high-conductance Ca2+-activated K+ channel. Nature 541:46-51
Hite, Richard K; Tao, Xiao; MacKinnon, Roderick (2017) Structural basis for gating the high-conductance Ca2+-activated K+ channel. Nature 541:52-57
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Wang, Weiwei; Touhara, Kouki K; Weir, Keiko et al. (2016) Cooperative regulation by G proteins and Na(+) of neuronal GIRK2 K(+) channels. Elife 5:

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