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

• Published in: Biochemical and biophysical research communications Vol. 482; no. 4; pp. 1135 - 1140
• Main Authors: Leipold, Enrico, Ullrich, Florian, Thiele, Markus, Tietze, Alesia A., Terlau, Heinrich, Imhof, Diana, Heinemann, Stefan H.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 22.01.2017
• Subjects: Channel block; Cone snails; Conotoxin; 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; Neurotoxin; Pain; Patch clamp; Peptides - chemistry; Potassium Channel Blockers - chemistry; Protein Domains; Shaker Superfamily of Potassium Channels - antagonists & inhibitors; Pain; Cone snails; NaV channel; Neurotoxin; Patch clamp; TTX; Conotoxin; KV channel; Channel block
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2016.11.170

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. [Display omitted] •μ-Conopeptides typically inhibit voltage-gated Na+ channels.•μ-PIIA and μ-SIIIA also block KV1.2 and KV1.6 voltage-gated K+ channels.•Subtype specificity is mediated by the channel's pore and turret domain.•μ-Conotoxins display marked target promiscuity.