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Biochem Biophys Res Commun. 2017 Jan 22;482(4):1135-1140. doi: 10.1016/j.bbrc.2016.11.170. Epub 2016 Dec 2.

Subtype-specific block of voltage-gated K+ channels by μ-conopeptides.

Author information

1
Center for Molecular Biomedicine, Department of Biophysics, Friedrich Schiller University Jena & Jena University Hospital, Hans-Knöll-Straße 2, D-07745 Jena, Germany.
2
Department of Organic Chemistry, Technical University of Darmstadt, D-64287 Darmstadt, Germany.
3
Institute of Physiology, Christian Albrechts University of Kiel, D-24098 Kiel, Germany.
4
Department of Pharmaceutical Chemistry I, Pharmaceutical Institute, University of Bonn, D-53119 Bonn, Germany.
5
Center for Molecular Biomedicine, Department of Biophysics, Friedrich Schiller University Jena & Jena University Hospital, Hans-Knöll-Straße 2, D-07745 Jena, Germany. Electronic address: Stefan.H.Heinemann@uni-jena.de.

Abstract

The neurotoxic cone snail peptide μ-GIIIA specifically blocks skeletal muscle voltage-gated sodium (NaV1.4) channels. The related conopeptides μ-PIIIA and μ-SIIIA, however, exhibit a wider activity spectrum by also inhibiting the neuronal NaV channels NaV1.2 and NaV1.7. Here we demonstrate that those μ-conopeptides with a broader target range also antagonize select subtypes of voltage-gated potassium channels of the KV1 family: μ-PIIIA and μ-SIIIA inhibited KV1.1 and KV1.6 channels in the nanomolar range, while being inactive on subtypes KV1.2-1.5 and KV2.1. Construction and electrophysiological evaluation of chimeras between KV1.5 and KV1.6 revealed that these toxins block KV channels involving their pore regions; the subtype specificity is determined in part by the sequence close to the selectivity filter but predominantly by the so-called turret domain, i.e. the extracellular loop connecting the pore with transmembrane segment S5. Conopeptides μ-SIIIA and μ-PIIIA, thus, are not specific for NaV channels, and the known structure of some KV channel subtypes may provide access to structural insight into the molecular interaction between μ-conopeptides and their target channels.

KEYWORDS:

Channel block; Cone snails; Conotoxin; Neurotoxin; Pain; Patch clamp

PMID:
27916464
DOI:
10.1016/j.bbrc.2016.11.170
[Indexed for MEDLINE]

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