title: Effects of I(Ks) channel inhibitors in insulin-secreting INS-1 cells.
abstract: 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.
authors.affiliation: Institute of Neurophysiology, University of Köln, Robert Koch Strasse 39, 50931 Cologne, Germany. susanne.ullrich@uni-tuebingen.de
authors.forename: Susanne
authors.initials: S
authors.lastname: Ullrich
authors.forename: Jiping
authors.initials: J
authors.lastname: Su
authors.forename: Felicia
authors.initials: F
authors.lastname: Ranta
authors.forename: Oliver H
authors.initials: OH
authors.lastname: Wittekindt
authors.forename: Frederic
authors.initials: F
authors.lastname: Ris
authors.forename: Martin
authors.initials: M
authors.lastname: Rösler
authors.forename: Uwe
authors.initials: U
authors.lastname: Gerlach
authors.forename: Dirk
authors.initials: D
authors.lastname: Heitzmann
authors.forename: Richard
authors.initials: R
authors.lastname: Warth
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
mesh_terms: 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
chemical_list: 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