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

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

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.

MeSH terms

  • Conotoxins / chemistry*
  • Electrophysiology
  • HEK293 Cells
  • Humans
  • Kv1.1 Potassium Channel / antagonists & inhibitors*
  • Kv1.2 Potassium Channel / antagonists & inhibitors*
  • Kv1.4 Potassium Channel / antagonists & inhibitors*
  • Kv1.6 Potassium Channel / antagonists & inhibitors*
  • Neurons / metabolism
  • Peptides / chemistry
  • Potassium Channel Blockers / chemistry*
  • Protein Domains
  • Shaker Superfamily of Potassium Channels / antagonists & inhibitors*

Substances

  • Conotoxins
  • KCNA4 protein, human
  • KCNA6 protein, human
  • Kv1.2 Potassium Channel
  • Kv1.4 Potassium Channel
  • Kv1.6 Potassium Channel
  • Peptides
  • Potassium Channel Blockers
  • Shaker Superfamily of Potassium Channels
  • mu-conotoxin PIIIA
  • mu-conotoxin SmIIIA
  • conotoxin GIII
  • Kv1.1 Potassium Channel