Insulin secretion is mainly regulated by two electrophysiological events,depolarization initiated by the closure of adenosine triphosphate(ATP)-sensitive K^(+)(K_(ATP))channels and repolarization mediated by K^(+)effl...Insulin secretion is mainly regulated by two electrophysiological events,depolarization initiated by the closure of adenosine triphosphate(ATP)-sensitive K^(+)(K_(ATP))channels and repolarization mediated by K^(+)efflux.Quinine,a natural component commonly used for the treatment of malaria,has been reported to directly stimulate insulin release and lead to hypoglycemia in patients during treatment through inhibiting K_(ATP)channels.In this study,we verified the insulinotropic effect of quinine on the isolated mouse pancreatic islets.We also revealed that low-dose quinine(<20μM)did not directly provoke Ca^(2+)spikes or insulin secretion under low-glucose conditions but potentiated Ca^(2+)influx and insulin secretion induced by high glucose,which cannot be explained by K_(ATP)inhibition.KCNH6(hERG2)is a voltage-dependent K^(+)(Kv)channel that plays a critical role in the repolarization of pancreaticβcells.Patch clamp experiments showed that quinine inhibited hERG channels at low micromolar concentrations.However,whether quinine can target KCNH6 to potentiate glucose-induced insulin secretion remains unclear.Here,we showed that in vivo administration of low-dose quinine(25 mg/kg)improved glucose tolerance and increased glucose-induced insulin release in wild-type control mice but not in Kcnh6-β-cell-specific knockout(βKO)mice.Consistently,in vitro treatment of primary isletβcells with low-dose quinine(10μM)prolonged action potential duration and augmented glucose-induced Ca^(2+)influx in the wild-type control group but not in the Kcnh6-βKO group.Our results demonstrate that KCNH6 plays an important role in low-dose quinine-potentiated insulin secretion and provide new insights into KCNH6-targeted drug development.展开更多
基金supported by grants from the National Natural Science Foundation of China(82070890 to J.L.and 81930019 to J.-K.Y.)Beijing Natural Science Foundation(7232230 to J.L.).
文摘Insulin secretion is mainly regulated by two electrophysiological events,depolarization initiated by the closure of adenosine triphosphate(ATP)-sensitive K^(+)(K_(ATP))channels and repolarization mediated by K^(+)efflux.Quinine,a natural component commonly used for the treatment of malaria,has been reported to directly stimulate insulin release and lead to hypoglycemia in patients during treatment through inhibiting K_(ATP)channels.In this study,we verified the insulinotropic effect of quinine on the isolated mouse pancreatic islets.We also revealed that low-dose quinine(<20μM)did not directly provoke Ca^(2+)spikes or insulin secretion under low-glucose conditions but potentiated Ca^(2+)influx and insulin secretion induced by high glucose,which cannot be explained by K_(ATP)inhibition.KCNH6(hERG2)is a voltage-dependent K^(+)(Kv)channel that plays a critical role in the repolarization of pancreaticβcells.Patch clamp experiments showed that quinine inhibited hERG channels at low micromolar concentrations.However,whether quinine can target KCNH6 to potentiate glucose-induced insulin secretion remains unclear.Here,we showed that in vivo administration of low-dose quinine(25 mg/kg)improved glucose tolerance and increased glucose-induced insulin release in wild-type control mice but not in Kcnh6-β-cell-specific knockout(βKO)mice.Consistently,in vitro treatment of primary isletβcells with low-dose quinine(10μM)prolonged action potential duration and augmented glucose-induced Ca^(2+)influx in the wild-type control group but not in the Kcnh6-βKO group.Our results demonstrate that KCNH6 plays an important role in low-dose quinine-potentiated insulin secretion and provide new insights into KCNH6-targeted drug development.
