Diethyldithiocarbamate-mediated zinc ion chelation reveals role of Ca(v)2.3 channels in glucagon secretion

摘要

Peptide-hormone secretion is partially triggered by Ca2+ influx through voltage-gated Ca2+ channels (VGCCs) and gene inactivation of Zn2+-sensitive Ca(v)2.3-type VGCCs is associated with disturbed glucose homeostasis in mice. Zn2+ has been implicated in pancreatic islet cell crosstalk and recent findings indicate that sudden cessation of Zn2+ supply during hypoglycemia triggers glucagon secretion in rodents. Here we show that diethyldithiocarbamate (DEDTC), a chelating agent for Zn2+ and other group IIB metal ions, differentially affects blood glucose and serum peptide hormone level in wild-type mice and mice lacking the Ca(v)2.3-subunit Fasting glucose and glucagon level were significantly higher in Ca(v)2.3-deficient compared to wild-type mice, while DEDTC Zn2+-chelation produced a significant and correlated increase of blood glucose and serum glucagon concentration in wild-type but not Ca(v)2.3-deficient mice. Glucose tolerance tests revealed severe glucose intolerance in Zn2+-depleted Ca(v)2.3-deficient but not vehicle-treated Ca(v)2.3-deficient or Zn2+-depleted wildtype mice. Collectively, these findings indicate that Ca(v)2.3 channels are critically involved in the Zn2+-mediated suppression of glucagon secretion during hyperglycemia. Especially under conditions of Zn2+ deficiency, ablation or dysfunction of Ca(v)2.3 channels may lead to severe disturbances in glucose homeostasis. (C) 2015 Elsevier B.V. All rights reserved.