Nature Biotechnology 23, 1289 - 1293 (2005)
Published online: 18 September 2005; | doi:10.1038/nbt1148
Generation of functional ion-channel tools by E3 targetingShang-Zhong Xu1, Fanning Zeng1, Ming Lei2, Jing Li1, Bin Gao3, Chenliang Xiong4, Asipu Sivaprasadarao1
& David J Beech11
Membrane and Systems Biology Research Institute, University of Leeds, Leeds, LS2 9JT, UK. 2
University Laboratory of Physiology, University of Oxford, OX1 3PT, UK. 3
Rheumatology Unit, Institute of Child Health, University College London, London WC1N 1EH, UK. 4
Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, P.R. China.
Correspondence should be addressed to David J Beech d.j.beech@leeds.ac.uk Here we describe a strategy for generating ion-channel inhibitors. It takes advantage of antibody specificity combined with a pattern recognition approach that targets the third extracellular region (E3) of a channel. To test the concept, we first focused on TRPC5, a member of the transient receptor potential (TRP) calcium channel family, the study of which has been hindered by poor pharmacological tools. Extracellular application of E3-targeted anti-TRPC5 antibody led to a specific TRPC5 inhibitor, enabling TRPC5 to be distinguished from its closest family members, and TRPC5 function to be explored in a relatively intractable physiological system. E3 targeting was further applied to voltage-gated sodium channels, leading to discovery of a subtype-specific inhibitor of NaV1.5. These examples illustrate the potential power of E3 targeting as a systematic method for producing gene-type specific ion-channel inhibitors for use in routine assays on cells or tissues from a range of species and having therapeutic potential.
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