Voltage-gated ion channels are responsible for the conduction of action potentials in nerve and muscle, and are critical in the timing of rhythmic electrical activity in the heart, smooth muscle, and secretory cells, among others. The mechanism by which changes in membrane potential lead to the opening and closing of these channels is partly understood: it involves the rearrangement of charges within the channel proteins, at least in part by the movement of protein domains such as the 'S4'region that is seen in the peptide sequences of sodium, potassium and calcium channels. The present work will employ patch-clamp recordings of ionic currents and gating currents from channels expressed in Xenopus oocytes, and will use three novel analytical approaches to analyze the recordings. The work will also exploit newly-discovered mutations in Shaker potassium channels that perturb the voltage-gating process and have already revealed new aspects of that process. The goal is to answer fundamental questions about the mechanism of voltage gating in channels, including: (1) How many voltage sensing domains are there in the Shaker channels, and where are they in the primary sequence? (2) How do these domains interact to cause channel opening? (3) What is the coupling between voltage-sensing domains and the channel's pore?
| Bai, Jun-Ping; Moeini-Naghani, Iman; Zhong, Sheng et al. (2017) Current carried by the Slc26 family member prestin does not flow through the transporter pathway. Sci Rep 7:46619 |
| Sigworth, Fred J (2016) Principles of cryo-EM single-particle image processing. Microscopy (Oxf) 65:57-67 |
| Jensen, Katrine Hommelhoff; Sigworth, Fred J; Brandt, Sami Sebastian (2016) Removal of Vesicle Structures From Transmission Electron Microscope Images. IEEE Trans Image Process 25:540-52 |
| Jensen, Katrine Hommelhoff; Brandt, Sami Sebastian; Shigematsu, Hideki et al. (2016) Statistical modeling and removal of lipid membrane projections for cryo-EM structure determination of reconstituted membrane proteins. J Struct Biol 194:49-60 |
| Dvornek, Nicha C; Sigworth, Fred J; Tagare, Hemant D (2015) SubspaceEM: A fast maximum-a-posteriori algorithm for cryo-EM single particle reconstruction. J Struct Biol 190:200-14 |
| Singh, Satinder K; Sigworth, Fred J (2015) Cryo-EM: Spinning the Micelles Away. Structure 23:1561 |
| Tagare, Hemant D; Kucukelbir, Alp; Sigworth, Fred J et al. (2015) Directly reconstructing principal components of heterogeneous particles from cryo-EM images. J Struct Biol 191:245-62 |
| Kucukelbir, Alp; Sigworth, Fred J; Tagare, Hemant D (2014) Quantifying the local resolution of cryo-EM density maps. Nat Methods 11:63-5 |
| Liu, Yunhui; Sigworth, Fred J (2014) Automatic cryo-EM particle selection for membrane proteins in spherical liposomes. J Struct Biol 185:295-302 |
| Shigematsu, H; Sigworth, F J (2013) Noise models and cryo-EM drift correction with a direct-electron camera. Ultramicroscopy 131:61-9 |
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