title: Carvedilol inhibits Kir2.3 channels by interference with PIP₂-channel interaction.
abstract: Carvedilol, a β- and α-adrenoceptor blocker, is used to treat congestive heart failure, mild to moderate hypertension, and myocardial infarction. It has been proposed to block K(ATP) channels by binding to the bundle crossing region at a domain including cysteine at position 166, and thereby plugging the pore region. However, carvedilol was reported not to affect Kir2.1 channels, which lack 166 Cys. Here, we demonstrate that carvedilol inhibits Kir2.3 carried current by an alternative mechanism. Carvedilol inhibited Kir2.3 channels with at least 100 fold higher potency (IC(50)=0.49 μM) compared to that for Kir2.1 (IC(50)>50 μM). Kir2.3 channel inhibition was concentration-dependent and voltage-independent. Increasing Kir2.3 channel affinity for PIP(2), by a I213L point mutation, decreased the inhibitory effect of carvedilol more than twentyfold (IC(50)=11.1 μM). In the presence of exogenous PIP(2), Kir2.3 channel inhibition by carvedilol was strongly reduced (80 vs. 2% current inhibition). These results suggest that carvedilol, as other cationic amphiphilic drugs, inhibits Kir2.3 channels by interfering with the PIP(2)-channel interaction.
authors.affiliation: Unidad de Investigación Carlos Méndez del Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Mexico. tania@ucol.mx
authors.forename: Tania
authors.initials: T
authors.lastname: Ferrer
authors.forename: Daniela
authors.initials: D
authors.lastname: Ponce-Balbuena
authors.forename: Angélica
authors.initials: A
authors.lastname: López-Izquierdo
authors.forename: Ivan A
authors.initials: IA
authors.lastname: Aréchiga-Figueroa
authors.forename: Teun P
authors.initials: TP
authors.lastname: de Boer
authors.forename: Marcel A G
authors.initials: MA
authors.lastname: van der Heyden
authors.forename: José A
authors.initials: JA
authors.lastname: Sánchez-Chapula
mesh_terms: D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D057809:HEK293 Cells; D006801:Humans; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D017354:Point Mutation; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D011412:Propanolamines / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects
chemical_list: D002227:Carbazoles; C099489:KCNJ4 protein, human; C489461:Kir2.1 channel; D019269:Phosphatidylinositol 4,5-Diphosphate; D026902:Potassium Channel Blockers; D024661:Potassium Channels, Inwardly Rectifying; D011412:Propanolamines; D000077261:Carvedilol