EFFECT OF ENGLITAZONE ON K-ATP AND CALCIUM-ACTIVATED NONSELECTIVE CATION CHANNELS IN CRI-G1 INSULIN-SECRETING CELLS

1 The effects of englitazone sodium, an antidiabetic agent, on ion cha nnel activity in the CRI-G1 insulin secreting cell line was examined b y use of the patch clamp technique. 2 Application of englitazone to th e outside of CRI-G1 cells in the whole-cell recording configuration pr oduced concentration-dependent inhibition of K-ATP currents with an IC 50 value of 8 mu M. The inhibition of the K+ current was not affected by the removal of Mg2+ ions from or the addition of trypsin to the sol ution bathing the intracellular surface of the cell membrane. 3 Englit azone also inhibited K-ATP channel activity in recordings from inside out excised membrane patches. The concentration-dependence of inhibiti on was identical to that observed in whole-cell recordings and was vol tage-independent. Single channel recordings confirmed that neither the absence or presence of Mg2+ ions nor the addition of trypsin at the i ntracellular surface of the membrane influenced the inhibition of K-AT P channels by englitazone. 4 Englitazone also inhibited Ca2+-activated non-selective cation (NSCa) channels in inside-out patches in a conce ntration-dependent and voltage-independent manner with an IC50 value o f 10 mu M. In comparison, the non-sulphonylurea K-ATP channel blocker ciclazindol produced a slight voltage-dependent inhibition of the NSCa channel at a concentration of 20 mu M. 5 In whole-cell recordings eng litazone, at a relatively high concentration (50 mu M) in comparison w ith that required to block K-ATP and NSCa channels, inhibited voltage- activated Ca2+ currents by 33% but did not inhibit voltage-activated K + and Na+ currents. 6 It is concluded that englitazone is a novel bloc ker of NSCa and K-ATP channels. The inhibition of K-ATP channels occur s following procedures that dissociate sulphonylurea receptor coupling to the channel. The equipotent and voltage-independent inhibition of NSCa and K-ATP channels by englitazone may indicate a common mechanism of block.