title: Engineered specific and high-affinity inhibitor for a subtype of inward-rectifier K+ channels.
abstract: Inward-rectifier K(+) (Kir) channels play many important biological roles and are emerging as important therapeutic targets. Subtype-specific inhibitors would be useful tools for studying the channels' physiological functions. Unfortunately, available K(+) channel inhibitors generally lack the necessary specificity for their reliable use as pharmacological tools to dissect the various kinds of K(+) channel currents in situ. The highly conserved nature of the inhibitor targets accounts for the great difficulty in finding inhibitors specific for a given class of K(+) channels or, worse, individual subtypes within a class. Here, by modifying a toxin from the honey bee venom, we have successfully engineered an inhibitor that blocks Kir1 with high (1 nM) affinity and high (>250-fold) selectivity over many commonly studied Kir subtypes. This success not only yields a highly desirable tool but, perhaps more importantly, demonstrates the practical feasibility of engineering subtype-specific K(+) channel inhibitors.
authors.affiliation: Department of Physiology, University of Pennsylvania, 3700 Hamilton Walk, Philadelphia, PA 19104, USA.
authors.forename: Yajamana
authors.initials: Y
authors.lastname: Ramu
authors.forename: Yanping
authors.initials: Y
authors.lastname: Xu
authors.forename: Zhe
authors.initials: Z
authors.lastname: Lu
mesh_terms: D000818:Animals; D001514:Bee Venoms / Q000235:genetics* / Q000494:pharmacology*; D008958:Models, Molecular; D016296:Mutagenesis; D009865:Oocytes / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors*; D015202:Protein Engineering / Q000379:methods*; D014981:Xenopus
chemical_list: D001514:Bee Venoms; C086989:KCNJ1 protein, human; D024661:Potassium Channels, Inwardly Rectifying; C029738:tertiapin