title: Subtype-specific block of voltage-gated K+channels by μ-conopeptides.
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 NaVchannels 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 KVchannels 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 NaVchannels, and the known structure of some KVchannel subtypes may provide access to structural insight into the molecular interaction between μ-conopeptides and their target channels.
authors.affiliation: Center for Molecular Biomedicine, Department of Biophysics, Friedrich Schiller University Jena & Jena University Hospital, Hans-Knöll-Straße 2, D-07745 Jena, Germany.
authors.forename: Enrico
authors.initials: E
authors.lastname: Leipold
authors.affiliation: Center for Molecular Biomedicine, Department of Biophysics, Friedrich Schiller University Jena & Jena University Hospital, Hans-Knöll-Straße 2, D-07745 Jena, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Ullrich
authors.affiliation: Center for Molecular Biomedicine, Department of Biophysics, Friedrich Schiller University Jena & Jena University Hospital, Hans-Knöll-Straße 2, D-07745 Jena, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Thiele
authors.affiliation: Department of Organic Chemistry, Technical University of Darmstadt, D-64287 Darmstadt, Germany.
authors.forename: Alesia A
authors.initials: AA
authors.lastname: Tietze
authors.affiliation: Institute of Physiology, Christian Albrechts University of Kiel, D-24098 Kiel, Germany.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Terlau
authors.affiliation: Department of Pharmaceutical Chemistry I, Pharmaceutical Institute, University of Bonn, D-53119 Bonn, Germany.
authors.forename: Diana
authors.initials: D
authors.lastname: Imhof
authors.affiliation: 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.
authors.forename: Stefan H
authors.initials: SH
authors.lastname: Heinemann
mesh_terms: D020916:Conotoxins / Q000737:chemistry*; D004594:Electrophysiology; D057809:HEK293 Cells; D006801:Humans; D051662:Kv1.1 Potassium Channel / Q000037:antagonists & inhibitors*; D051663:Kv1.2 Potassium Channel / Q000037:antagonists & inhibitors*; D051665:Kv1.4 Potassium Channel / Q000037:antagonists & inhibitors*; D051667:Kv1.6 Potassium Channel / Q000037:antagonists & inhibitors*; D009474:Neurons / Q000378:metabolism; D010455:Peptides / Q000737:chemistry; D026902:Potassium Channel Blockers / Q000737:chemistry*; D000072417:Protein Domains; D051637:Shaker Superfamily of Potassium Channels / Q000037:antagonists & inhibitors*
chemical_list: D020916:Conotoxins; C496977:KCNA4 protein, human; C064389:KCNA6 protein, human; D051663:Kv1.2 Potassium Channel; D051665:Kv1.4 Potassium Channel; D051667:Kv1.6 Potassium Channel; D010455:Peptides; D026902:Potassium Channel Blockers; D051637:Shaker Superfamily of Potassium Channels; C112845:mu-conotoxin PIIIA; C470785:mu-conotoxin SmIIIA; C046101:conotoxin GIII; D051662:Kv1.1 Potassium Channel
keywords: Channel block; Cone snails; Conotoxin; Neurotoxin; Pain; Patch clamp