Antisense oligodeoxynucleotides of sulfonylurea receptors inhibit ATP-sensitive K + channels in cultured neonatal rat ventricular cells

Jan 23, 1999Pflugers Archiv : European journal of physiology

Antisense molecules targeting sulfonylurea receptors reduce ATP-sensitive potassium channel activity in newborn rat heart cells

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Abstract

The maximal KATP currents induced by metabolic inhibition were 48.9 ± 2.8 pA/pF in control neonatal rat ventricular cells.

Treatment with antisense oligonucleotides targeting SUR1 or SUR2 significantly reduced KATP currents in comparison to control cells.
KATP currents measured in cells treated with antisense-SUR1 were 34.3 ± 3.5 pA/pF, while those with antisense-SUR2 were 23.5 ± 3.4 pA/pF.
Scramble oligonucleotides did not affect KATP currents, confirming the specificity of the antisense treatment.
The study indicates that both SUR1 and SUR2 subtypes may be essential components of functional KATP channels in these cells.
Outward K+ currents were stimulated by diazoxide in control cells, but this response varied depending on the specific SUR subtype present.

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To identify the functional sulfonylurea receptor (SUR), a subunit of the adenosine 5'-triphosphate (ATP)-sensitive K+ (KATP) channels, in neonatal rat ventricular cells, such cells in primary culture were treated for 6 days with antisense (AS) oligodeoxynucleotides (ODNs) complementary to the mRNA for SURs. For quantification, single-channel (inside-out patches) and whole-cell currents were measured using the patch-clamp technique. The maximal KATP currents (at 0 mV) induced by metabolic inhibition were 48.9+/-2.8 pA/pF in control (n=48), 34.3+/-3.5 pA/pF in AS-SUR1 (n=21, P<0.05 vs control), and 23.5+/-3.4 pA/pF in AS-SUR2 (n=17, P<0.01 vs control). As a control, scramble oligonucleotides had no effect. The fast Na+ current and inward-rectifying K+ current were not affected by AS-SURs. Treatment with both AS-SUR1 and AS-SUR2 had no additive effects on inhibition of KATP currents compared with AS-SUR2 alone. The single-channel conductance, open probability, and kinetics (in ATP-free solution) were not significantly different between control, AS-SUR1, and AS-SUR2. These results suggest that treatment with AS-ODN for SUR1 or SUR2 reduced the number of functional KATP channels. Furthermore, in four out of seven control cells tested, outward K+ currents were stimulated by diazoxide, which is a potent K+ channel-opening drug for the constructed SUR1/Kir6.2 and SUR2B/Kir6.2 channels, but not for the SUR2A/Kir6.2 channel. Therefore, in neonatal rat ventricular cells, both SUR2 and SUR1 subtypes could be integral components of the functional KATP channels. The larger population of KATP channels may be constructed with SUR2, whereas a smaller population may be constructed with a combination of SUR1 and SUR2.

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Antisense oligodeoxynucleotides of sulfonylurea receptors inhibit ATP-sensitive K + channels in cultured neonatal rat ventricular cells

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