title: A novel high-affinity inhibitor for inward-rectifier K+ channels.
abstract: Inward-rectifier K+ channels are a group of highly specialized K+ channels that accomplish a variety of important biological tasks. Inward-rectifier K+ channels differ from voltage-activated K+ channels not only functionally but also structurally. Each of the four subunits of the inward-rectifier K+ channels has only two instead of six transmembrane segments compared to the voltage-activated K+ channels. Thus far, there are no high-affinity ligands that directly target any inward-rectifier K+ channel. In the present study, we identified, purified, and synthesized a protein inhibitor of the inward-rectifier K+ channels. The inhibitor, called tertiapin, blocks a G-protein-gated channel (GIRK1/4) and the ROMK1 channel with nanomolar affinities, but a closely related channel, IRK1, is insensitive to tertiapin. Mutagenesis studies show that teritapin inhibits the channel by binding to the external end of the ion conduction pore.
authors.affiliation: Department of Physiology, University of Pennsylvania, Philadelphia 19104, USA.
authors.forename: W
authors.initials: W
authors.lastname: Jin
authors.forename: Z
authors.initials: Z
authors.lastname: Lu
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001514:Bee Venoms / Q000096:biosynthesis / Q000302:isolation & purification / Q000494:pharmacology*; D001516:Bees; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009865:Oocytes; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying; D017386:Sequence Homology, Amino Acid; D014982:Xenopus laevis
chemical_list: D001514:Bee Venoms; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; C029738:tertiapin