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Antibody-guided photoablation of voltage-gated potassium currents

A family of 40 mammalian voltage-gated potassium (Kv) channels control membrane excitability in electrically excitable cells. The contribution of individual Kv channel types to electrophysiological signaling has been difficult to assign, as few selective inhibitors exist for individual Kv subunits....

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Autores principales: Sack, Jon T., Stephanopoulos, Nicholas, Austin, Daniel C., Francis, Matthew B., Trimmer, James S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3753605/
https://www.ncbi.nlm.nih.gov/pubmed/23940262
http://dx.doi.org/10.1085/jgp.201311023
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author Sack, Jon T.
Stephanopoulos, Nicholas
Austin, Daniel C.
Francis, Matthew B.
Trimmer, James S.
author_facet Sack, Jon T.
Stephanopoulos, Nicholas
Austin, Daniel C.
Francis, Matthew B.
Trimmer, James S.
author_sort Sack, Jon T.
collection PubMed
description A family of 40 mammalian voltage-gated potassium (Kv) channels control membrane excitability in electrically excitable cells. The contribution of individual Kv channel types to electrophysiological signaling has been difficult to assign, as few selective inhibitors exist for individual Kv subunits. Guided by the exquisite selectivity of immune system interactions, we find potential for antibody conjugates as selective Kv inhibitors. Here, functionally benign anti-Kv channel monoclonal antibodies (mAbs) were chemically modified to facilitate photoablation of K currents. Antibodies were conjugated to porphyrin compounds that upon photostimulation inflict localized oxidative damage. Anti-Kv4.2 mAb–porphyrin conjugates facilitated photoablation of Kv4.2 currents. The degree of K current ablation was dependent on photon dose and conjugate concentration. Kv channel photoablation was selective for Kv4.2 over Kv4.3 or Kv2.1, yielding specificity not present in existing neurotoxins or other Kv channel inhibitors. We conclude that antibody–porphyrin conjugates are capable of selective photoablation of Kv currents. These findings demonstrate that subtype-specific mAbs that in themselves do not modulate ion channel function are capable of delivering functional payloads to specific ion channel targets.
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spelling pubmed-37536052014-03-01 Antibody-guided photoablation of voltage-gated potassium currents Sack, Jon T. Stephanopoulos, Nicholas Austin, Daniel C. Francis, Matthew B. Trimmer, James S. J Gen Physiol Communication A family of 40 mammalian voltage-gated potassium (Kv) channels control membrane excitability in electrically excitable cells. The contribution of individual Kv channel types to electrophysiological signaling has been difficult to assign, as few selective inhibitors exist for individual Kv subunits. Guided by the exquisite selectivity of immune system interactions, we find potential for antibody conjugates as selective Kv inhibitors. Here, functionally benign anti-Kv channel monoclonal antibodies (mAbs) were chemically modified to facilitate photoablation of K currents. Antibodies were conjugated to porphyrin compounds that upon photostimulation inflict localized oxidative damage. Anti-Kv4.2 mAb–porphyrin conjugates facilitated photoablation of Kv4.2 currents. The degree of K current ablation was dependent on photon dose and conjugate concentration. Kv channel photoablation was selective for Kv4.2 over Kv4.3 or Kv2.1, yielding specificity not present in existing neurotoxins or other Kv channel inhibitors. We conclude that antibody–porphyrin conjugates are capable of selective photoablation of Kv currents. These findings demonstrate that subtype-specific mAbs that in themselves do not modulate ion channel function are capable of delivering functional payloads to specific ion channel targets. The Rockefeller University Press 2013-09 /pmc/articles/PMC3753605/ /pubmed/23940262 http://dx.doi.org/10.1085/jgp.201311023 Text en © 2013 Sack et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Communication
Sack, Jon T.
Stephanopoulos, Nicholas
Austin, Daniel C.
Francis, Matthew B.
Trimmer, James S.
Antibody-guided photoablation of voltage-gated potassium currents
title Antibody-guided photoablation of voltage-gated potassium currents
title_full Antibody-guided photoablation of voltage-gated potassium currents
title_fullStr Antibody-guided photoablation of voltage-gated potassium currents
title_full_unstemmed Antibody-guided photoablation of voltage-gated potassium currents
title_short Antibody-guided photoablation of voltage-gated potassium currents
title_sort antibody-guided photoablation of voltage-gated potassium currents
topic Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3753605/
https://www.ncbi.nlm.nih.gov/pubmed/23940262
http://dx.doi.org/10.1085/jgp.201311023
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