The long-term objective of this project is to understand the mechanisms of voltage-dependent gating. The study will focus on a variety of voltage-dependent K+ channels, including ones that open upon membrane depolarization and another that opens upon membrane hyperpolarization. It will also study a voltage-dependent phophatase enzyme. Structural methods including X-ray crystallography and electron microscopy will be used to determine atomic structures. Functional methods including electrophysiology will be used to correlate channel function with the structural analysis. Voltage sensing is an important biochemical mechanism in living cells. This mechanism in ion channels enables membrane voltage to feed back on itself. Voltage feedback allows the propagation of electrical impulses known as action potentials. Action, potentials underlie information transfer in the nervous system as well as skeletal muscle and cardiac muscle contraction, among other processes. Therefore voltage-dependent channels are important targets for future pharmaceutical agents that could potentially treat afflictions such as seizure disorders, cardiac arrhythmias and musculoskeletal disorders. Pharmacological manipulation of ion channels in the autonomic nervous system and its targets (such as smooth muscle and endocrine organs) also promises to offer new therapies for the treatment of asthma, hypertension and diabetes. The mechanistic and structural studies proposed here will hopefully lead to the development of new therapies in the future.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Study Section
Biophysics of Neural Systems Study Section (BPNS)
Program Officer
Rivera-Rentas, Alberto L
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Rockefeller University
Other Domestic Higher Education
New York
United States
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Lee, Chia-Hsueh; MacKinnon, Roderick (2018) Activation mechanism of a human SK-calmodulin channel complex elucidated by cryo-EM structures. Science 360:508-513
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
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
Whicher, Jonathan R; MacKinnon, Roderick (2016) Structure of the voltage-gated K? channel Eag1 reveals an alternative voltage sensing mechanism. Science 353:664-9
Su, Zhenwei; Brown, Emily C; Wang, Weiwei et al. (2016) Novel cell-free high-throughput screening method for pharmacological tools targeting K+ channels. Proc Natl Acad Sci U S A 113:5748-53
Touhara, Kouki K; Wang, Weiwei; MacKinnon, Roderick (2016) The GIRK1 subunit potentiates G protein activation of cardiac GIRK1/4 hetero-tetramers. Elife 5:
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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