title: Identification of P2X4 receptor-specific residues contributing to the ivermectin effects on channel deactivation.
abstract: 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.
authors.affiliation: Department of Cellular and Molecular Neuroendocrinology, Institute of Physiology, ASCR, Prague, Czech Republic.
authors.forename: Irena
authors.initials: I
authors.lastname: Jelínková
authors.forename: Zonghe
authors.initials: Z
authors.lastname: Yan
authors.forename: Zhaodong
authors.initials: Z
authors.lastname: Liang
authors.forename: Sachin
authors.initials: S
authors.lastname: Moonat
authors.forename: Jan
authors.initials: J
authors.lastname: Teisinger
authors.forename: Stanko S
authors.initials: SS
authors.lastname: Stojilkovic
authors.forename: Hana
authors.initials: H
authors.lastname: Zemková
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D000595:Amino Acid Sequence; D000818:Animals; D000977:Antiparasitic Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007559:Ivermectin / Q000737:chemistry* / Q000494:pharmacology; D008969:Molecular Sequence Data; D051381:Rats; D018048:Receptors, Purinergic P2 / Q000737:chemistry*; D058848:Receptors, Purinergic P2X4; D017386:Sequence Homology, Amino Acid; D014364:Tryptophan / Q000737:chemistry; D014633:Valine / Q000737:chemistry
chemical_list: D000977:Antiparasitic Agents; C548226:P2RX4 protein, human; C548228:P2rx4 protein, rat; D018048:Receptors, Purinergic P2; D058848:Receptors, Purinergic P2X4; D007559:Ivermectin; D014364:Tryptophan; D000255:Adenosine Triphosphate; D014633:Valine