Neurons and other excitable cells use ion channel proteins to generate electrical and chemical signals. Understanding the structure and functional mechanisms of voltage-activated ion channels is of particular significance because these proteins generate nerve impulses, providing a critical solution to the biological problem of signaling rapidly over long distances. A mechanistic understanding of these proteins is also of medical significance because they are involved in many disease, and are widely targeted by therapeutic drugs. Recent X-ray structures of voltage-activated potassium (Kv) channels have led to new ideas about how interactions between voltage-activated ion channels and the surrounding membrane are crucial for function of these channels, a theme that we be exploring in our studies. We propose to use several approaches to explore the structural basis of the interaction of toxins, small molecules and lipids with S1-S4 domains from voltage-activated ion channels embedded in membrane environments. Although much of this aim will focus on S1-S4 domains in Kv channels, within this context we also seek to extend our studies to include transient receptor potential (TRP) channels, a fascinating family of sensory channels with diverse functions, ranging from sensing temperature and pain, to detecting natural products. We will attempt to define S1-S4 domains in TRP channels, and explore the interactions of their amphipathic activators within the membrane.

Project Start
Project End
Budget Start
Budget End
Support Year
17
Fiscal Year
2013
Total Cost
$2,115,778
Indirect Cost
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State
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Bae, Chanhyung; Anselmi, Claudio; Kalia, Jeet et al. (2016) Structural insights into the mechanism of activation of the TRPV1 channel by a membrane-bound tarantula toxin. Elife 5:
Zhang, Feng; Hanson, Sonya M; Jara-Oseguera, Andres et al. (2016) Engineering vanilloid-sensitivity into the rat TRPV2 channel. Elife 5:
Jara-Oseguera, Andres; Bae, Chanhyung; Swartz, Kenton J (2016) An external sodium ion binding site controls allosteric gating in TRPV1 channels. Elife 5:
Gupta, Kanchan; Zamanian, Maryam; Bae, Chanhyung et al. (2015) Tarantula toxins use common surfaces for interacting with Kv and ASIC ion channels. Elife 4:e06774
Hanson, Sonya M; Newstead, Simon; Swartz, Kenton J et al. (2015) Capsaicin interaction with TRPV1 channels in a lipid bilayer: molecular dynamics simulation. Biophys J 108:1425-34
Fleming, Michael S; Vysochan, Anna; Paixão, Sόnia et al. (2015) Cis and trans RET signaling control the survival and central projection growth of rapidly adapting mechanoreceptors. Elife 4:e06828
Toombes, Gilman E S; Swartz, Kenton J (2014) Divining the design principles of voltage sensors. J Gen Physiol 143:139-44
Mihailescu, Mihaela; Krepkiy, Dmitriy; Milescu, Mirela et al. (2014) Structural interactions of a voltage sensor toxin with lipid membranes. Proc Natl Acad Sci U S A 111:E5463-70
Kalia, Jeet; Swartz, Kenton J (2013) Exploring structure-function relationships between TRP and Kv channels. Sci Rep 3:1523
Swartz, Kenton J (2013) The scorpion toxin and the potassium channel. Elife 2:e00873

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