Abstract: Pain has been the most frequent reason for physician consultation, and chronic pain syndromes can severely undermine patients'qualities of life. Current analgesics are limited in that many patients with chronic pain syndromes or neuropathic pains do not respond to the drugs. Therefore there is a pressing need for new drug development along with a better understanding of the mechanism of the proteins that are the targets of these analgesics. Voltage-gated sodium channel subtype 1.7 is a newly emerging target for analgesic development. Using innovative approaches, I plan to characterize novel therapeutic regions of the voltage-gated sodium channel by a combination of tools, including chemical screening, structural biology, and electrophysiology. The proposed studies will provide new insights into future analgesic development as well as fundamental processes of voltage-gated sodium channels. Public Health Relevance: Pain is a major symptom in many medical conditions and chronic pain syndromes can severely reduce quality of life. There is a clear clinical need for new analgesics with a new mechanism of action. The voltage-gated sodium channel subtype 1.7 (Nav1.7) is a newly emerging target for analgesics, as patients with loss-of-function mutations in Nav1.7 do not feel pain. My research proposal is to study Nav1.7 by developing pharmacological tools and characterizing the mechanism of voltage sensing. My proposed research, if successful, will pave the way for the development of new analgesics and further our understanding of the mechanisms of voltage sensing in voltage-gated sodium channels in health and in disease.
|Pitt, Geoffrey S; Lee, Seok-Yong (2016) Current view on regulation of voltage-gated sodium channels by calcium and auxiliary proteins. Protein Sci 25:1573-84|
|Zubcevic, Lejla; Herzik Jr, Mark A; Chung, Ben C et al. (2016) Cryo-electron microscopy structure of the TRPV2 ion channel. Nat Struct Mol Biol 23:180-186|
|Lee, Jun-Ho; Park, Chul-Kyu; Chen, Gang et al. (2014) A monoclonal antibody that targets a NaV1.7 channel voltage sensor for pain and itch relief. Cell 157:1393-404|
|Wang, Chaojian; Chung, Ben C; Yan, Haidun et al. (2014) Structural analyses of Ca²?/CaM interaction with NaV channel C-termini reveal mechanisms of calcium-dependent regulation. Nat Commun 5:4896|
|Johnson, Zachary Lee; Cheong, Cheom-Gil; Lee, Seok-Yong (2012) Crystal structure of a concentrative nucleoside transporter from Vibrio cholerae at 2.4?Å. Nature 483:489-93|
|Wang, Chaojian; Chung, Ben C; Yan, Haidun et al. (2012) Crystal structure of the ternary complex of a NaV C-terminal domain, a fibroblast growth factor homologous factor, and calmodulin. Structure 20:1167-76|