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Pore loop-mutated rat KIR6.1 and KIR6.2 suppress K_ATP current in rat cardiomyocytes

¹Department of Physiology, Centre Médical Universitaire, Geneva 1204, Switzerland; ²Sanofi-Synthelabo, 92500 Rueil Malmaison, France; and ³Department of Cardiovascular Sciences, University of Leicester, LE2 72X Leicester, United Kingdom

Submitted 21 January 2004 ; accepted in final form 18 March 2004

Cardiomyocytes express mRNA for all major subunits of ATP-sensitive potassium (K_ATP) channels: KIR6.1, KIR6.2, SUR1A, SUR2A, and SUR2B. It has remained controversial as to whether KIR6.1 may associate with KIR6.2 to form the tetrameric pore of K_ATP channels in cardiomyocytes. To explore this possibility, cultured rat cardiomyocytes were examined for an inhibition of K_ATP current by overexpression of pore loop-mutated (inactive) KIR6.x. Bicistronic plasmids were constructed encoding loop-mutated (AFA or SFG for GFG) rat KIR6.x followed by EGFP. In ventricular myocytes, the overexpression of KIR6.1SFG-pIRES₂-EGFP or KIR6.2AFA-pIRES₂-EGFP DNA caused, after 72 h, a major decrease of K_ATP current density of 85.8% and 82.7%, respectively (P < 0.01), relative to EGFP controls (59 ± 9 pA/pF). In atrial myocytes, overexpression of these pore-mutated KIR6.x by 6.0-fold and 10.6-fold, as assessed by quantitative immunohistochemistry, caused a decrease of K_ATP current density of 73.7% and 58.5%, respectively (P < 0.01). Expression of wild-type rat KIR6.2 increased the ventricular and atrial K_ATP current density by 58.3% and 42.9%, respectively (P < 0.01), relative to corresponding EGFP controls, indicating a reserve of SUR to accommodate increased KIR6.x trafficking to the sarcolemma. The results favor the view that KIR6.1 may associate with KIR6.2 to form heterotetrameric pores of native K_ATP channels in cardiomyocytes.

ATP-sensitive potassium channels; atrium; ventricle

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