Referenced in: none

Automatically associated channels: Kir6.2

Title: Carvedilol blocks cardiac KATP and KG but not IK1 channels by acting at the bundle-crossing regions.

Authors: Jun-ichi Kikuta, Masaru Ishii, Kentaro Kishimoto, Yoshihisa Kurachi

Journal, date & volume: Eur. J. Pharmacol., 2006 Jan 4 , 529, 47-54

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/16325804

Abstract
We examined the effects of carvedilol on cardiac inwardly rectifying K(+) (Kir) channels, i.e., ATP-sensitive (K(ATP)), G-protein-activated (K(G)) and background (I(K1)) Kir channels. We found that carvedilol effectively inhibits K(ATP) and K(G), but not I(K1) channels. Carvedilol inhibits K(ATP) channels reconstituted in HEK293 cells with Kir6.2 lacking the C-terminal 26 amino acids (Kir6.2DeltaC26), suggesting that carvedilol acts in the channel pore. A sequence comparison of the three channels revealed that a cysteine residue, C166, in the inner helix of Kir6.2 is conserved in both Kir6.xs (K(ATP)) and Kir3.xs (K(G)), but not in Kir2.xs (I(K1)). The mutation of this residue (C166A) made Kir6.2DeltaC26 resistant to the drug. Homology modeling and docking simulation suggested that interaction between carvedilol and the pore could be located at the cytosolic portion of the inner helix (bundle-crossing region) containing C166. This study shows that carvedilol blocks specific groups of Kir channels by interacting with the bundle-crossing region.