Evidence for the Inhibitory Actions of Curcuminoids on Delayed-Rectifier K+ Currents in Insulin-Secreting (INS-1) Cells

摘要

Curcuminoids are mainly composed of curcumin (CUR) demethoxycurcumin (DMC) bisdemethoxycurcumin (BDMC) CUR a principal constituent of the curcuminoids has been recently demonstrated to modulate various cellular signaling molecules and induce insulin release from pancreatic b-cells Diabetes mellitus occurs when the pancreatic b-cells produce insufficient amounts of the hormone insulin This causes high blood glucose levels which can lead to a number of complications if untreated However how curcuminoids exert any possible effects on membrane ion currents in insulin-secreting cells remains largely unclear There were recognized to be three major ion currents that is ATP-sensitive K+ channels voltage-gated Ca2+ channels and voltage-gated K+ channels operating in pancreatic b-cells and the most important ionic events in b-cell signaling The delayed-rectifier K+ (IK(DR)) channel can function as brake for glucose-stimulated insulin secretion The effects of curcuminoids on ion currents especially in IK(DR) in rat INS-1 insulinoma cells were therefore investigated in this study by using patch-clamp technique and the protein expression were detected by western blot The results showed that the INS-1 cells treated different concentrations of curcuminoids had no effect on the cell viability and KDR channels protein expression CUR suppressed the amplitude of IK(DR) in a time- state- and concentration-dependent manner in these cells and the inhibition was not reversed by diazoxide nicorandil or chlorotoxin The value of dissociation constant for CUR-induced suppression of IK(DR) in INS-1 cells was 1 26 uM Despite the inability of CUR to alter the activation rate of IK(DR) it accelerated current inactivation elicited by membrane depolarization Increasing CUR concentrations shifted the inactivation curve of IK(DR) to hyperpolarized potential and slowed the recovery of IK(DR) inactivation CUR DMC and BDMC exerted depressant actions on IK(DR) amplitude to a similar magnitude although DMC and BDMC did not increase current inactivation clearly CUR suppressed the peak amplitude of voltage-gated Na+ current CUR DMC and BDMC depolarized the resting potential and increased firing frequency of action potentials There was no significant difference in the protein expression of protein kinase B (Akt) and phosphorylated protein kinase B (pAkt) among different concentrations of CUR DMC BDMC Taken these results together these effects can significantly contribute to their actions on functional activities of insulin-secreting cells if similar findings are found in vivo

獎項日期	2017 7月 18
原文	English
監督員	Sheng-Nan Wu (Supervisor)