The long-term objective of this project is to understand the mechanisms of K + channel gating, that is, how the opening of K + channels is regulated in living cells. Potassium channels play a central role in many different cellular processes including the production of electrical impulses in the nervous system, the control of heart rate, blood pressure, and the secretion of hormones such as insulin. For these reasons, a deeper understanding of how K+ channels open and close - based on their chemistry and structure -will eventually enhance our ability to treat many illnesses that afflict humans, including seizure disorders, cardiac arrhythmias, hypertension, and asthma. A wide range of techniques will be applied to the study of K + channel gating, including molecular biology, protein biochemistry, electrophysiology, and X-ray crystallography. Three fundamentally different gating mechanisms will be studied: channel opening induced by Ca 2+ binding, by G-protein binding, and by membrane voltage. The first of these mechanisms underlies muscle contraction and signal processing in the nervous system, the second mechanism controls heart rate and neurotransmitter responses, and the third is responsible for generating electrical impulses known as action potentials in both nervous and non-nervous cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM043949-16
Application #
6924681
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Shapiro, Bert I
Project Start
1990-04-01
Project End
2007-07-31
Budget Start
2005-08-01
Budget End
2006-07-31
Support Year
16
Fiscal Year
2005
Total Cost
$437,473
Indirect Cost
Name
Rockefeller University
Department
Biology
Type
Other Domestic Higher Education
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
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
Hite, Richard K; MacKinnon, Roderick (2017) Structural Titration of Slo2.2, a Na+-Dependent K+ Channel. Cell 168:390-399.e11
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:
Whicher, Jonathan R; MacKinnon, Roderick (2016) Structure of the voltage-gated K? channel Eag1 reveals an alternative voltage sensing mechanism. Science 353:664-9

Showing the most recent 10 out of 59 publications