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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Toombes, Gilman E S; Swartz, Kenton J (2014) Divining the design principles of voltage sensors. J Gen Physiol 143:139-44
Kalia, Jeet; Swartz, Kenton J (2013) Exploring structure-function relationships between TRP and Kv channels. Sci Rep 3:1523
Kalia, Jeet; Swartz, Kenton J (2013) Common principles of voltage-dependent gating for Hv and Kv channels. Neuron 77:214-6
Swartz, Kenton J (2013) The scorpion toxin and the potassium channel. Elife 2:e00873
Milescu, Mirela; Lee, Hwa C; Bae, Chan Hyung et al. (2013) Opening the shaker K+ channel with hanatoxin. J Gen Physiol 141:203-16
Kalia, Jeet; Swartz, Kenton J (2013) The design principle of paddle motifs in voltage sensors. Nat Struct Mol Biol 20:534-5
Lee, Seungkyu; Milescu, Mirela; Jung, Hyun Ho et al. (2010) Solution structure of GxTX-1E, a high-affinity tarantula toxin interacting with voltage sensors in Kv2.1 potassium channels . Biochemistry 49:5134-42
Krepkiy, Dmitriy; Mihailescu, Mihaela; Freites, J Alfredo et al. (2009) Structure and hydration of membranes embedded with voltage-sensing domains. Nature 462:473-9
Milescu, Mirela; Bosmans, Frank; Lee, Seungkyu et al. (2009) Interactions between lipids and voltage sensor paddles detected with tarantula toxins. Nat Struct Mol Biol 16:1080-5
Swartz, Kenton J (2008) Sensing voltage across lipid membranes. Nature 456:891-7

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