Effects of I(Ks) channel inhibitors in insulin-secreting INS-1 cells.
Potassium channels regulate insulin secretion. The closure of K(ATP) channels leads to membrane depolarisation, which triggers Ca(2+) influx and stimulates insulin secretion. The subsequent activation of K(+) channels terminates secretion. We examined whether KCNQ1 channels are expressed in pancreatic beta-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(+) 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(50)) of 37 microM. The other sulfonamide analogue HMR1556 inhibited 48% of the outward current with an IC(50) of 7 microM. The chromanol 293B had no effect on tolbutamide-sensitive K(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(+) channels, influence action potential duration and frequency and thus insulin secretion.
Ullrich
Susanne
S
Institute of Neurophysiology, University of Köln, Robert Koch Strasse 39, 50931 Cologne, Germany. susanne.ullrich@uni-tuebingen.de
Su
Jiping
J
Ranta
Felicia
F
Wittekindt
Oliver H
OH
Ris
Frederic
F
Rösler
Martin
M
Gerlach
Uwe
U
Heitzmann
Dirk
D
Warth
Richard
R
Lang
Florian
F
D015761:4-Aminopyridine; D000818:Animals; D045744:Cell Line, Tumor; D002839:Chromans / Q000494:pharmacology*; D015870:Gene Expression; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000502:physiology*; D051657:KCNQ1 Potassium Channel / Q000502:physiology*; D008564:Membrane Potentials; D051381:Rats; D013449:Sulfonamides / Q000494:pharmacology*; D019789:Tetraethylammonium; D014044:Tolbutamide
D002839:Chromans; C420023:HMR 1556; D007328:Insulin; D051657:KCNQ1 Potassium Channel; D013449:Sulfonamides; C103474:6-cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dimethylchromane; D019789:Tetraethylammonium; D014044:Tolbutamide; D015761:4-Aminopyridine