Effects of IKs channel inhibitors in insulin-secreting INS-1 cells

Potassium channels regulate insulin secretion. The closure of K^sub ATP^ channels leads to membrane depolarisation, which triggers Ca^sup 2+^ influx and stimulates insulin secretion. The subsequent activation of K^sup +^ channels terminates secretion. We examined whether KCNQ1 channels are expressed in pancreatic β-cells and analysed their functional role. Using RT/PCR cellular mRNA of KCNQ1 but not of KCNE1 channels was detected in INS-1 cells. Effects of two sulfonamide analogues, 293B and HMR1556, inhibitors of KCNQ1 channels, were examined on voltage-activated outwardly rectifying K^sup +^ currents using the patch-clamp method. It was found that 293B inhibited 60% of whole-cell outward currents induced by voltage pulses from -70 to +50 mV with a concentration for half-maximal inhibition (IC^sub 50^) of 37 μM. The other sulfonamide analogue HMR1556 inhibited 48% of the outward current with an IC^sub 50^ of 7 μM. The chromanol 293B had no effect on tolbutamide-sensitive K^sub ATP^ channels. Action potentials induced by current injections were broadened and after-repolarisation was attenuated by 293B. Insulin secretion in the presence but not in the absence of tolbutamide was significantly increased by 293B. These results suggest that 293B- and HMR1556-sensitive channels, probably in concert with other voltage-activated K^sup +^ channels, influence action potential duration and frequency and thus insulin secretion.[PUBLICATION ABSTRACT]