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

Abstract

The effects of the chaotrophic anion perchlorate (ClO4-) on glucose-induced electrical activity, exocytosis and ion channel activity in mouse pancreatic B-cells were investigated by patch-clamp recordings and capacitance measurements. ClO4- stimulated glucose-induced electrical activity and increased the action potential frequency by 70% whilst not affecting the membrane potential when applied in the presence of a subthreshold concentration of the sugar. ClO4- did not influence ATP-dependent K (KATP) channel activity and voltage-gated delayed K+ current. Similarly, ClO4- had no effect on Ca2+-dependent exocytosis. The stimulation of electrical activity and insulin secretion was instead attributable to an enhancement of the whole-cell Ca2+ current. This effect was particularly pronounced at voltages around the threshold for action potential initiation and a doubling of the current amplitude was observed at -30 mV. This was due to a 7-mV shift in the gating of the Ca2+ current towards negative voltages. The action of ClO4- was more pronounced when added in the presence of 0.1 mM BAY K8644, whereas no stimulation was observed when applied at a maximal concentration of the agonist (1 mM). Single-channel recordings revealed that the effect of ClO4- on whole-cell 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 K8644-like action on Ca2+ channel gating.

Glucose dependence of insulinotropic actions of pituitary adenylate cyclase-activating polypeptide in insulin-secreting INS-1 cells

“…The idea that this effect is due to the peptide interfering with the voltage-gated Ca2+ channels is consistent with the fact that PACAP-27 overall increases depolarization-elicited Ca2+ influx by @35% (Figs. 2, 4,6), in a fashion reminiscent of the action of the chaotrophic anion perchlorate [28]. Taken together, these actions account for 1.41.35=1.9 or 90% stimulation, close to the increase in insulin release observed when experimenting at 10 mM and 20 mM glucose (Fig.…”

“…The action potentials in the INS-1 cells are Ca2+ dependent and the observed effect can thus be extrapolated to correspond to an enhanced Ca2+ influx which in turn associates with the acceleration of insulin release. This PACAP-induced acceleration of electrical activity is reminiscent of the effects of the chaotrophic anion perchlorate [28]. When increasing the extracellular glucose concentration, the generated pattern of electrical activity was so irregular that a straightforward analysis of the glucose-dependent action of PACAP-27 was not possible (not shown).…”

Isoform-specific regulation of mood behavior and pancreatic β cell and cardiovascular function by L-type Ca2+ channels

“…This pharmacological phenotype was achieved without detectable alterations in channel gating or Ca v 1.2 α1 expression. High-affinity DHP binding in brain was reduced to a level (20%) known to be associated with Ca v 1.3 (1,30 (15,33), such drugs theoretically allow stimulation of insulin secretion in a glucose-sensitive manner (33). Our data clearly revealed that Ca v 1.3 LTCCs are not suitable targets for insulin secretagogues because we found no evidence for the acute regulation of β cell Ca 2+ currents or insulin secretion by DHPs in Ca v 1.2DHP -/-mice.…”

Anion-Sensitive Regions of L-Type CaV1.2 Calcium Channels Expressed in HEK293 Cells

“…One poorly understood mechanism involves the effects of anions on I Ca . Replacing Cl − with various substituting anions influences many Ca 2+ -mediated processes including contractility of cardiac and skeletal muscle, hormone secretion, and neurotransmitter release [8]–[16]. An important contributor to these anion effects is the modulation of L-type Ca 2+ currents (I Ca ) [8]–[10], [17], [18].…”