In response to membrane potential depolarization, voltage-dependent potassium channels undergo a series of conformational changes from a non-conducting state (closed) to an activated (conducting) state. K+ channel function has been associated with such basic cellular functions as the regulation of electrical activity, signal transduction and osmotic balance. In higher organisms, K+ channel dysfunction may lead to uncontrolled periods of electrical hyperexcitability, like epileptic episodes, myotonia and cardiac arrhythmia. Consequently, efforts to understand K+ channel structure function and dynamics relate directly to human health and disease. The continuing long-term goal of this project is to further understand the molecular mechanisms of gating in voltage-dependent channels, by focusing on the analysis of K+ channel gating in prokaryotic systems. Specifically we will address the following key questions: What are the molecular entities determining channel activity? How energy (in the form of specific ligand binding or transmembrane electric field) is transduced into protein motion? How different parts of the channel interact to define open channel activity? We plan to study these problems by combining spectroscopic techniques (EPR NMR and Fluorescence), X-ray crystallography and electrophysiological methods. This particular strategy has proven very successful over the previous grant period, leading to i) Direct structural determinations of the types of molecular movements underlying KcsA gating mechanism and structural information on the role of the selectivity filter in gating; and 2) A structural analysis of the native conformation of KvAP, the voltage-dependent channel from Aeropyrum pernix. We intend to continue these structure-function studies while extending them using new experimental approaches. In addition, we will focus our attention on a newly characterized hyperpolarization-activated six-transmembrane segment (6TM) channel from Methanococcus janschii (MVP). This proposal should open new experimental avenues that will contribute to our understanding of biologically important events such as electrical signaling, signal transduction and ion channel gating. ? ? ?

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Biochemistry and Biophysics of Membranes Study Section (BBM)
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Shapiro, Bert I
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University of Chicago
Schools of Medicine
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Li, Jing; Ostmeyer, Jared; Cuello, Luis G et al. (2018) Rapid constriction of the selectivity filter underlies C-type inactivation in the KcsA potassium channel. J Gen Physiol 150:1408-1420
Zhao, Ruiming; Kennedy, Kelleigh; De Blas, Gerardo A et al. (2018) Role of human Hv1 channels in sperm capacitation and white blood cell respiratory burst established by a designed peptide inhibitor. Proc Natl Acad Sci U S A 115:E11847-E11856
Kratochvil, Huong T; Maj, Micha?; Matulef, Kimberly et al. (2017) Probing the Effects of Gating on the Ion Occupancy of the K+ Channel Selectivity Filter Using Two-Dimensional Infrared Spectroscopy. J Am Chem Soc 139:8837-8845
Vandenberg, Jamie I; Perozo, Eduardo; Allen, Toby W (2017) Towards a Structural View of Drug Binding to hERG K+ Channels. Trends Pharmacol Sci 38:899-907
Li, Jing; Ostmeyer, Jared; Boulanger, Eliot et al. (2017) Chemical substitutions in the selectivity filter of potassium channels do not rule out constricted-like conformations for C-type inactivation. Proc Natl Acad Sci U S A 114:11145-11150
Kratochvil, Huong T; Carr, Joshua K; Matulef, Kimberly et al. (2016) Instantaneous ion configurations in the K+ ion channel selectivity filter revealed by 2D IR spectroscopy. Science 353:1040-1044
Li, Qufei; Shen, Rong; Treger, Jeremy S et al. (2015) Resting state of the human proton channel dimer in a lipid bilayer. Proc Natl Acad Sci U S A 112:E5926-35
Li, Qufei; Wanderling, Sherry; Paduch, Marcin et al. (2014) Structural mechanism of voltage-dependent gating in an isolated voltage-sensing domain. Nat Struct Mol Biol 21:244-52
Li, Qufei; Wanderling, Sherry; Sompornpisut, Pornthep et al. (2014) Structural basis of lipid-driven conformational transitions in the KvAP voltage-sensing domain. Nat Struct Mol Biol 21:160-6
Raghuraman, H; Islam, Shahidul M; Mukherjee, Soumi et al. (2014) Dynamics transitions at the outer vestibule of the KcsA potassium channel during gating. Proc Natl Acad Sci U S A 111:1831-6

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