Ultrasensitive pharmacological characterisation of the voltage-gated potassium channel K(V)1.3 studied by single-molecule fluorescence microscopy

Histochem Cell Biol. 2002 Mar;117(3):197-202. doi: 10.1007/s00418-001-0374-y. Epub 2002 Jan 30.

Abstract

The determination of pharmacologically relevant constants is crucial in order to understand the effects of compounds interacting with various membrane receptors. In this report we study a venom component of the Central American scorpion Centruroides limbatus, a short peptide termed hongotoxin(1) (HgTX(1)), which specifically binds to the voltage-gated potassium channel K(V)1.3 at a molecular stoichiometry of 1:1. A toxin analogue (HgTX(1)-A19C) was subjected to fluorescence labelling studies with Cy5. Utilising an ultrasensitive microscopic method (single-dye tracing; SDT) we were able to directly visualise HgTX(1)-A19C-Cy5 binding to the voltage-gated potassium channel K(V)1.3 on Jurkat cells at the single molecule level. For the first time, this approach allowed the determination of both the dissociation constant (K(D)) and the off-rate (k(off)) of HgTX(1)-A19C-Cy5 on living cells. In order to validate this novel approach, the data obtained with SDT were correlated to radioligand binding studies performed under identical conditions using a radioiodinated HgTX(1) analogue.

MeSH terms

  • Binding, Competitive / drug effects
  • Cell Line
  • Dose-Response Relationship, Drug
  • Humans
  • Iodine Radioisotopes
  • Jurkat Cells
  • Kv1.3 Potassium Channel
  • Microscopy, Fluorescence / instrumentation
  • Microscopy, Fluorescence / methods*
  • Mutation
  • Neurotoxins / genetics
  • Neurotoxins / metabolism
  • Neurotoxins / pharmacology
  • Potassium Channels / genetics
  • Potassium Channels / metabolism*
  • Potassium Channels, Voltage-Gated*
  • Radioligand Assay
  • Scorpion Venoms / genetics
  • Scorpion Venoms / metabolism
  • Scorpion Venoms / pharmacology*
  • Transfection

Substances

  • Iodine Radioisotopes
  • KCNA3 protein, human
  • Kv1.3 Potassium Channel
  • Neurotoxins
  • Potassium Channels
  • Potassium Channels, Voltage-Gated
  • Scorpion Venoms
  • hongotoxin 1