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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Ballesteros, Angela; Swartz, Kenton J (2018) Lipids surf the groove in scramblases. Proc Natl Acad Sci U S A 115:7648-7650
Ballesteros, Angela; Fenollar-Ferrer, Cristina; Swartz, Kenton Jon (2018) Structural relationship between the putative hair cell mechanotransduction channel TMC1 and TMEM16 proteins. Elife 7:
Bae, Chanhyung; Jara-Oseguera, Andres; Swartz, Kenton J (2018) TRPM channels come into focus. Science 359:160-161
Matthies, Doreen; Bae, Chanhyung; Toombes, Gilman Es et al. (2018) Single-particle cryo-EM structure of a voltage-activated potassium channel in lipid nanodiscs. Elife 7:
Zhang, Feng; Jara-Oseguera, Andres; Chang, Tsg-Hui et al. (2018) Heat activation is intrinsic to the pore domain of TRPV1. Proc Natl Acad Sci U S A 115:E317-E324
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:

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