title: Rosiglitazone selectively inhibits K(ATP)  channels by acting on the K(IR) 6 subunit.
abstract: OBJECTIVE
  Rosiglitazone is an anti-diabetic drug acting as an insulin sensitizer. We recently found that rosiglitazone also inhibits the vascular isoform of ATP-sensitive K(+) channels and compromises vasodilatory effects of β-adrenoceptor activation and pinacidil. As its potency for the channel inhibition is in the micromolar range, rosiglitazone may be used as an effective K(ATP) channel inhibitor for research and therapeutic purposes. Therefore, we performed experiments to determine whether other isoforms of K(ATP) channels are also sensitive to rosiglitazone and what their sensitivities are.
  
  
  METHODS
  K(IR) 6.1/SUR2B, K(IR) 6.2/SUR1, K(IR) 6.2/SUR2A, K(IR) 6.2/SUR2B and K(IR) 6.2ΔC36 channels were expressed in HEK293 cells and were studied using patch-clamp techniques.
  
  
  RESULTS
  Rosiglitazone inhibited all isoforms of K(ATP) channels in excised patches and in the whole-cell configuration. Its IC(50) was 10 µmol·L(-1) for the K(IR) 6.1/SUR2B channel and ∼45 µmol·L(-1) for K(IR) 6.2/SURx channels. Rosiglitazone also inhibited K(IR) 6.2ΔC36 channels in the absence of the sulphonylurea receptor (SUR) subunit, with potency (IC(50) = 45 µmol·L(-1) ) almost identical to that for K(IR) 6.2/SURx channels. Single-channel kinetic analysis showed that the channel inhibition was mediated by augmentation of the long-lasting closures without affecting the channel open state and unitary conductance. In contrast, rosiglitazone had no effect on K(IR) 1.1, K(IR) 2.1 and K(IR) 4.1 channels, suggesting that the channel inhibitory effect is selective for K(IR) 6.x channels.
  
  
  CONCLUSIONS
  These results suggest a novel K(ATP) channel inhibitor that acts on the pore-forming K(IR) 6.x subunit, affecting the channel gating.
authors.affiliation: Department of Biology, Georgia State University, Atlanta, Georgia 30302-4010, USA. cjiang@gsu.edu
authors.forename: Lei
authors.initials: L
authors.lastname: Yu
authors.forename: Xin
authors.initials: X
authors.lastname: Jin
authors.forename: Ningren
authors.initials: N
authors.lastname: Cui
authors.forename: Yang
authors.initials: Y
authors.lastname: Wu
authors.forename: Zhenda
authors.initials: Z
authors.lastname: Shi
authors.forename: Daling
authors.initials: D
authors.lastname: Zhu
authors.forename: Chun
authors.initials: C
authors.lastname: Jiang
mesh_terms: D057809:HEK293 Cells; D006801:Humans; D054086:KATP Channels / Q000037:antagonists & inhibitors* / Q000502:physiology; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D021122:Protein Subunits / Q000037:antagonists & inhibitors* / Q000502:physiology; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D054086:KATP Channels; D026902:Potassium Channel Blockers; D021122:Protein Subunits; D045162:Thiazolidinediones; D014665:Vasodilator Agents; D000077154:Rosiglitazone