title: IonFlux: a microfluidic patch clamp system evaluated with human Ether-à-go-go related gene channel physiology and pharmacology.
abstract: Ion channel assays are essential in drug discovery, not only for identifying promising new clinical compounds, but also for minimizing the likelihood of potential side effects. Both applications demand optimized throughput, cost, and predictive accuracy of measured membrane current changes evoked or modulated by drug candidates. Several competing electrophysiological technologies are available to address this demand, but important gaps remain. We describe the industrial application of a novel microfluidic-based technology that combines compounds, cells, and buffers on a single, standard well plate. Cell trapping, whole cell, and compound perfusion are accomplished in interconnecting microfluidic channels that are coupled to pneumatic valves, which emancipate the system from robotics, fluidic tubing, and associated maintenance. IonFlux™ is a state-of-the-art, compact system with temperature control and continuous voltage clamp for potential application in screening for voltage- and ligand-gated ion channel modulators. Here, ensemble recordings of the IonFlux system were validated with the human Ether-à-go-go related gene (hERG) channel (stably expressed in a Chinese hamster ovary cell line), which has established biophysical and pharmacological characteristics in other automated planar patch systems. We characterized the temperature dependence of channel activation and its reversal potential. Concentration response characteristics of known hERG blockers and control compounds obtained with the IonFlux system correlated with literature and internal data obtained on this cell line with the QPatch HT system. Based on the biophysical and pharmacological data, we conclude that the IonFlux system offers a novel, versatile, automated profiling, and screening system for ion channel targets with the benefit of temperature control.
authors.affiliation: Preclinical Safety Profiling, Center for Proteomic Chemistry, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 02139, USA.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Golden
authors.forename: Nianzhen
authors.initials: N
authors.lastname: Li
authors.forename: Qin
authors.initials: Q
authors.lastname: Chen
authors.forename: Tony
authors.initials: T
authors.lastname: Lee
authors.forename: Tanner
authors.initials: T
authors.lastname: Nevill
authors.forename: Xueying
authors.initials: X
authors.lastname: Cao
authors.forename: Juliette
authors.initials: J
authors.lastname: Johnson
authors.forename: Gül
authors.initials: G
authors.lastname: Erdemli
authors.forename: Cristian
authors.initials: C
authors.lastname: Ionescu-Zanetti
authors.forename: Laszlo
authors.initials: L
authors.lastname: Urban
authors.forename: Mats
authors.initials: M
authors.lastname: Holmqvist
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000295:instrumentation / Q000379:methods; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000502:physiology*; D006801:Humans; D044085:Microfluidics / Q000295:instrumentation / Q000379:methods*; D018408:Patch-Clamp Techniques / Q000295:instrumentation* / Q000379:methods; D026902:Potassium Channel Blockers / Q000494:pharmacology*
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; D026902:Potassium Channel Blockers