Identification of P2X4 receptor-specific residues contributing to the ivermectin effects on channel deactivation

Biochem Biophys Res Commun. 2006 Oct 20;349(2):619-25. doi: 10.1016/j.bbrc.2006.08.084. Epub 2006 Aug 22.


Ivermectin (IVM) applied extracellularly increases the sensitivity of P2X4 receptor (P2X4R) to ATP, enhances the maximum current amplitudes, and greatly prolongs the deactivation kinetics. In this manuscript, we focused on identification of receptor-specific residues responsible for IVM effects on channel gating using the wild-type rat homomeric P2X4R, several chimeric P2X2/P2X4 receptors, and single-point P2X4R-specific mutants in the ectodomain and two transmembrane domains. Experiments with chimeric receptors revealed that the Val49-Val61 but not the Val64-Tyr315 ectodomain sequence is important for the effects of IVM on channel deactivation. Receptor-specific mutations placed in the Gly29-Val61 and Asp338-Leu358 regions showed the importance of Trp50, Val60, and Val357 residues in IVM regulation of the rate of channel deactivation, but not on the maximum current amplitude. These results suggest that the transmembrane domains and the nearby ectodomain region contribute to the effects of IVM on channel deactivation.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / chemistry
  • Amino Acid Sequence
  • Animals
  • Antiparasitic Agents / pharmacology
  • Dose-Response Relationship, Drug
  • Humans
  • Ivermectin / chemistry*
  • Ivermectin / pharmacology
  • Molecular Sequence Data
  • Rats
  • Receptors, Purinergic P2 / chemistry*
  • Receptors, Purinergic P2X4
  • Sequence Homology, Amino Acid
  • Tryptophan / chemistry
  • Valine / chemistry


  • Antiparasitic Agents
  • P2RX4 protein, human
  • P2rx4 protein, rat
  • Receptors, Purinergic P2
  • Receptors, Purinergic P2X4
  • Ivermectin
  • Tryptophan
  • Adenosine Triphosphate
  • Valine