Carvedilol inhibits Kir2.3 channels by interference with PIP(2)-channel interaction.

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Ferrer T, Ponce-Balbuena D, Lopez-Izquierdo A, Arechiga-Figueroa IA, de Boer TP, van der Heyden MA, Sanchez-Chapula JA

Carvedilol inhibits Kir2.3 channels by interference with PIP(2)-channel interaction.

Eur J Pharmacol. 2011 Oct 1;668(1-2):72-7. doi: 10.1016/j.ejphar.2011.05.067. Epub 2011 Jun 6.

PubMed ID

21663737 [ View in PubMed

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Abstract

Carvedilol, a beta- and alpha-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 muM) compared to that for Kir2.1 (IC(50)>50 muM). 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 muM). 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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Carvedilol	Inward rectifier potassium channel 2	Protein	Humans	Unknown	Inhibitor	Details
Carvedilol	Inward rectifier potassium channel 4	Protein	Humans	Unknown	Inhibitor	Details