The orchestrated activity of voltage-gated ion channels enables cells in the nervous system,and throughout biology, to generate and propagate electrical signals. A primary focus of the laboratory is to investigate the structure of voltage-gated potassium channels and to understand how structural rearrangements in the voltage-sensing domains open and close the ion conduction pore. We have been using large-scale scanning mutagenesis to explore the secondary and tertiary structure of elements within the voltage-sensing domains. Using the structure of the KcsA potassium channel as a guide, we have begun to map the protein-protein interface between voltage-sensing and pore domains. Another approach exploits protein toxins that modify voltage-dependent gating to probe the structure and mechanics of regions involved in gating. Our work on the toxins has involved studying the mechanism by which these toxins modify gating, solving the three-dimensional structure of the toxins (through collaboration), and mapping their receptors. We are now beginning to use these gating modifier toxins to address fundamental questions about the structures involved in gating and on the type of conformational rearrangements that occur with changes in membrane voltage. In addition, the laboratory is also interested in understanding how the molecular design of voltage-gated ion channels allows them to fulfill specific physiological roles. We have been developing new pharmacological probes against specific types of voltage-gated ion channels so that their functional contribution to complex electrical phenomena can be better examined.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Intramural Research (Z01)
Project #
1Z01NS002945-06
Application #
6671395
Study Section
(NIND)
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2002
Total Cost
Indirect Cost
City
State
Country
United States
Zip Code
Zhang, Feng; Hanson, Sonya M; Jara-Oseguera, Andres et al. (2016) Engineering vanilloid-sensitivity into the rat TRPV2 channel. Elife 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
Soler-Llavina, Gilberto J; Chang, Tsg-Hui; Swartz, Kenton J (2006) Functional interactions at the interface between voltage-sensing and pore domains in the Shaker K(v) channel. Neuron 52:623-34
Swartz, Kenton J (2006) Greasing the gears of potassium channels. Nat Chem Biol 2:401-2
Silberberg, Shai D; Chang, Tsg-Hui; Swartz, Kenton J (2005) Secondary structure and gating rearrangements of transmembrane segments in rat P2X4 receptor channels. J Gen Physiol 125:347-59
Kitaguchi, Tetsuya; Swartz, Kenton J (2005) An inhibitor of TRPV1 channels isolated from funnel Web spider venom. Biochemistry 44:15544-9
Swartz, Kenton J (2005) Structure and anticipatory movements of the S6 gate in Kv channels. J Gen Physiol 126:413-7
Phillips, L Revell; Milescu, Mirela; Li-Smerin, Yingying et al. (2005) Voltage-sensor activation with a tarantula toxin as cargo. Nature 436:857-60
Jung, Hoi Jong; Lee, Ju Yeon; Kim, Su Hwan et al. (2005) Solution structure and lipid membrane partitioning of VSTx1, an inhibitor of the KvAP potassium channel. Biochemistry 44:6015-23
Lee, Chul Won; Kim, Sunghwan; Roh, Soung Hun et al. (2004) Solution structure and functional characterization of SGTx1, a modifier of Kv2.1 channel gating. Biochemistry 43:890-7

Showing the most recent 10 out of 25 publications