title: Diethyldithiocarbamate-mediated zinc ion chelation reveals role of Cav2.3 channels in glucagon secretion.
abstract: 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.
authors.affiliation: Institute for Neurophysiology, University of Cologne, Robert-Koch-Str. 39, D-50931 Köln, Germany.
authors.forename: Irina
authors.initials: I
authors.lastname: Drobinskaya
authors.affiliation: Institute for Neurophysiology, University of Cologne, Robert-Koch-Str. 39, D-50931 Köln, Germany. Electronic address: felix@neumaier-net.de.
authors.forename: Felix
authors.initials: F
authors.lastname: Neumaier
authors.affiliation: Institute for Neurophysiology, University of Cologne, Robert-Koch-Str. 39, D-50931 Köln, Germany.
authors.forename: Alexey
authors.initials: A
authors.lastname: Pereverzev
authors.affiliation: Institute for Neurophysiology, University of Cologne, Robert-Koch-Str. 39, D-50931 Köln, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Hescheler
authors.affiliation: Institute for Neurophysiology, University of Cologne, Robert-Koch-Str. 39, D-50931 Köln, Germany. Electronic address: toni.schneider@uni-koeln.de.
authors.forename: Toni
authors.initials: T
authors.lastname: Schneider
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D020908:Calcium Channels, R-Type / Q000172:deficiency / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000172:deficiency / Q000378:metabolism*; D002614:Chelating Agents / Q000494:pharmacology*; D004050:Ditiocarb / Q000494:pharmacology*; D005215:Fasting / Q000097:blood; D005260:Female; D017353:Gene Deletion; D005934:Glucagon / Q000097:blood / Q000378:metabolism*; D005951:Glucose Tolerance Test; D057809:HEK293 Cells; D006801:Humans; D006946:Hyperinsulinism / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D015640:Ion Channel Gating / Q000187:drug effects; D007477:Ions; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008954:Models, Biological; D015032:Zinc / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; C498916:Cacna1e protein, mouse; D020908:Calcium Channels, R-Type; D027682:Cation Transport Proteins; D002614:Chelating Agents; D007328:Insulin; D007477:Ions; D005934:Glucagon; D004050:Ditiocarb; D015032:Zinc
keywords: Gene inactivation; Peptide hormone release; Pharmacoresistant Ca(2+) channel; Toxin-resistant current