Diethyldithiocarbamate-mediated zinc ion chelation reveals role of Cav2.3 channels in glucagon secretion

Biochim Biophys Acta. 2015 May;1853(5):953-64. doi: 10.1016/j.bbamcr.2015.01.001. Epub 2015 Jan 17.


Peptide-hormone secretion is partially triggered by Ca2+ influx through voltage-gated Ca2+ channels (VGCCs) and gene inactivation of Zn2+-sensitive Cav2.3-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 Cav2.3-subunit. Fasting glucose and glucagon level were significantly higher in Cav2.3-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 Cav2.3-deficient mice. Glucose tolerance tests revealed severe glucose intolerance in Zn2+-depleted Cav2.3-deficient but not vehicle-treated Cav2.3-deficient or Zn2+-depleted wildtype mice. Collectively, these findings indicate that Cav2.3 channels are critically involved in the Zn2+-mediated suppression of glucagon secretion during hyperglycemia. Especially under conditions of Zn2+ deficiency, ablation or dysfunction of Cav2.3 channels may lead to severe disturbances in glucose homeostasis.

Keywords: Gene inactivation; Peptide hormone release; Pharmacoresistant Ca(2+) channel; Toxin-resistant current.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / metabolism
  • Body Weight / drug effects
  • Calcium Channels, R-Type / deficiency
  • Calcium Channels, R-Type / metabolism*
  • Cation Transport Proteins / deficiency
  • Cation Transport Proteins / metabolism*
  • Chelating Agents / pharmacology*
  • Ditiocarb / pharmacology*
  • Fasting / blood
  • Female
  • Gene Deletion
  • Glucagon / blood
  • Glucagon / metabolism*
  • Glucose Tolerance Test
  • HEK293 Cells
  • Humans
  • Hyperinsulinism / metabolism
  • Insulin / metabolism
  • Insulin Secretion
  • Ion Channel Gating / drug effects
  • Ions
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / metabolism
  • Male
  • Mice
  • Models, Biological
  • Zinc / metabolism*


  • Blood Glucose
  • Cacna1e protein, mouse
  • Calcium Channels, R-Type
  • Cation Transport Proteins
  • Chelating Agents
  • Insulin
  • Ions
  • Glucagon
  • Ditiocarb
  • Zinc