title: The antimalarial drug mefloquine inhibits cardiac inward rectifier K+ channels: evidence for interference in PIP2-channel interaction.
abstract: The antimalarial drug mefloquine was found to inhibit the KATP channel by an unknown mechanism. Because mefloquine is a Cationic amphiphilic drug and is known to insert into lipid bilayers, we postulate that mefloquine interferes with the interaction between PIP2 and Kir channels resulting in channel inhibition. We studied the inhibitory effects of mefloquine on Kir2.1, Kir2.3, Kir2.3(I213L), and Kir6.2/SUR2A channels expressed in HEK-293 cells, and on IK1 and IKATP from feline cardiac myocytes. The order of mefloquine inhibition was Kir6.2/SUR2A ≈ Kir2.3 (IC50 ≈ 2 μM) > Kir2.1 (IC50 > 30 μM). Similar results were obtained in cardiac myocytes. The Kir2.3(I213L) mutant, which enhances the strength of interaction with PIP2 (compared to WT), was significantly less sensitive (IC50 = 9 μM). In inside-out patches, continuous application of PIP2 strikingly prevented the mefloquine inhibition. Our results support the idea that mefloquine interferes with PIP2-Kir channels interactions.
authors.affiliation: Unidad de Investigación Carlos Méndez del Centro Universitario de Investigaciones Biomédicas de la Universidad de Colima, Colima, Col. México.
authors.forename: Angélica
authors.initials: A
authors.lastname: López-Izquierdo
authors.forename: Daniela
authors.initials: D
authors.lastname: Ponce-Balbuena
authors.forename: Eloy G
authors.initials: EG
authors.lastname: Moreno-Galindo
authors.forename: Iván A
authors.initials: IA
authors.lastname: Aréchiga-Figueroa
authors.forename: Martín
authors.initials: M
authors.lastname: Rodríguez-Martínez
authors.forename: Tania
authors.initials: T
authors.lastname: Ferrer
authors.forename: Aldo A
authors.initials: AA
authors.lastname: Rodríguez-Menchaca
authors.forename: José A
authors.initials: JA
authors.lastname: Sánchez-Chapula
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000494:pharmacology*; D002415:Cats; D057809:HEK293 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D054086:KATP Channels / Q000037:antagonists & inhibitors; D015767:Mefloquine / Q000008:administration & dosage / Q000494:pharmacology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D026902:Potassium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors*
chemical_list: D000962:Antimalarials; D054086:KATP Channels; D019269:Phosphatidylinositol 4,5-Diphosphate; D026902:Potassium Channel Blockers; D024661:Potassium Channels, Inwardly Rectifying; D015767:Mefloquine