Perchlorate stimulates insulin secretion by shifting the gating of L-type Ca2+ currents in mouse pancreatic B-cells towards negative potentials

The effects of the chaotrophic anion perchlorate (ClO4-) on glucose-induced electrical activity, exocytosis and ion channel activity in mouse pancreat ic B-cells were investigated by patch-clamp recordings and capacitance meas urements. ClO4- stimulated glucose-induced electrical activity and increase d the action potential frequency by 70% whilst not affecting the membrane p otential when applied in the presence of a subthreshold concentration of th e sugar. ClO4- did not influence ATP-dependent K (K-ATP) channel activity a nd voltage-gated delayed K+ current. Similarly, ClO4- had no effect on Ca2-dependent exocytosis. The stimulation of electrical activity and insulin s ecretion was instead attributable to an enhancement of the whole-cell Ca2current. This effect was particularly pronounced at voltages around the thr eshold for action potential initiation and a doubling of the current amplit ude was observed at -30 mV. This was due to a 7-mV shift in the gating of t he Ca2+ current towards negative voltages. The action of ClO4- was more pro nounced when added in the presence of 0.1 mM BAY K8644, whereas no stimulat ion was observed when applied at a maximal concentration of the agonist (1 mM), Single-channel recordings revealed that the effect of ClO4- on whole-c ell currents was principally due to a 60% increase in the mean duration of the long openings and the number of active channels. We propose that ClO4- stimulates insulin secretion and electrical activity by exerting a BAY K864 4-like action on Ca2+ channel gating.