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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 Na(V)1.5. 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.

Original publication

DOI

10.1038/nbt1148

Type

Journal article

Journal

Nat Biotechnol

Publication Date

10/2005

Volume

23

Pages

1289 - 1293

Keywords

Antibodies, Monoclonal, Binding Sites, Drug Delivery Systems, Ion Channel Gating, Ion Channels, Protein Binding, Protein Engineering, TRPC Cation Channels