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.

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Chavan, Tanmay; Maduke, Merritt; Swartz, Kenton (2017) Protein ligands for studying ion channel proteins. J Gen Physiol 149:407-411
Toombes, Gilman E S; Swartz, Kenton J (2016) STRUCTURAL BIOLOGY. Twists and turns in gating ion channels with voltage. Science 353:646-7
Jara-Oseguera, Andres; Bae, Chanhyung; Swartz, Kenton J (2016) An external sodium ion binding site controls allosteric gating in TRPV1 channels. Elife 5:
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:
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
Fleming, Michael S; Vysochan, Anna; Paix√£o, S?nia et al. (2015) Cis and trans RET signaling control the survival and central projection growth of rapidly adapting mechanoreceptors. Elife 4:e06828
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
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
Toombes, Gilman E S; Swartz, Kenton J (2014) Divining the design principles of voltage sensors. J Gen Physiol 143:139-44

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