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(Circulation Research. 1995;77:1246-1253.)
© 1995 American Heart Association, Inc.

Articles

Anti-minK Antisense Decreases the Amplitude of the Rapidly Activating Cardiac Delayed Rectifier K⁺ Current

Tao Yang, Sabina Kupershmidt, Dan M. Roden

From the Vanderbilt University School of Medicine, Departments of Medicine and Pharmacology, Nashville, Tenn.

Correspondence to Dan M. Roden, MD, Director, Division of Clinical Pharmacology, 532 Medical Research Bldg, Vanderbilt University School of Medicine, Nashville, TN 37232-6602.

Abstract The rapidly and slowly activating delayed rectifier K⁺ currents (I_Kr and I_Ks, respectively), which have different physiological properties, have been identified in cardiac cells from several species, including humans. Although expression of the minimal K⁺ channel protein (minK) cDNA in some systems results in a current resembling I_Ks, the role of this gene product in channel function remains controversial. In atrial tumor myocytes (AT-1 cells), no I_Ks is recorded, but minK mRNA is detected, raising the possibility that expression of the minK gene serves an as-yet-unidentified function. In these experiments, AT-1 cells were exposed to antisense oligonucleotides targeting the 5' translation start site of the minK cDNA cloned from an AT-1 library. Cell size, I_Kr, and L-type and T-type Ca²⁺ currents were measured 24 to 48 hours after exposure and compared with data in cells exposed to the corresponding sense oligonucleotide or grown in medium only. Antisense oligonucleotide significantly reduced I_Kr compared with sense and medium-only control cells in 0 of 2 experiments (n=3 to 6 cells per treatment in each experiment) at 50 nmol/L, 1 of 2 at 250 nmol/L, 6 of 6 at 1000 nmol/L, and 2 of 2 at 10 000 nmol/L. At 1000 nmol/L, maximum tail current in antisense-exposed cells was 2.5±0.1 pA/pF (mean±SEM, n=28, 6 separate experiments), 6.6±0.4 pA/pF in sense-exposed cells (n=27), 5.4±0.6 pA/pF in medium-only cells (n=21), and 5.8±0.7 pA/pF in cells exposed to a random oligonucleotide (n=9). I_Kr activation, rectification, deactivation, and sensitivity to the blocker dofetilide were unaffected. Two different antisense oligonucleotides produced the same effect, and there was no effect of antisense treatment on cell size or on L- or T-type Ca²⁺ currents. These data indicate that in AT-1 cells, expression of the minK gene plays a role in determining I_Kr amplitude.

Key Words: delayed rectifier K⁺ current • minimal K⁺ channel protein • AT-1 cells

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