CaV2.3 calcium channels control second-phase insulin release

J Clin Invest. 2005 Jan;115(1):146-54. doi: 10.1172/JCI22518.


Concerted activation of different voltage-gated Ca( (2+) ) channel isoforms may determine the kinetics of insulin release from pancreatic islets. Here we have elucidated the role of R-type Ca(V)2.3 channels in that process. A 20% reduction in glucose-evoked insulin secretion was observed in Ca(V)2.3-knockout (Ca(V)2.3(-/-)) islets, close to the 17% inhibition by the R-type blocker SNX482 but much less than the 77% inhibition produced by the L-type Ca(2+) channel antagonist isradipine. Dynamic insulin-release measurements revealed that genetic or pharmacological Ca(V)2.3 ablation strongly suppressed second-phase secretion, whereas first-phase secretion was unaffected, a result also observed in vivo. Suppression of the second phase coincided with an 18% reduction in oscillatory Ca(2+) signaling and a 25% reduction in granule recruitment after completion of the initial exocytotic burst in single Ca(V)2.3(-/-) beta cells. Ca(V)2.3 ablation also impaired glucose-mediated suppression of glucagon secretion in isolated islets (27% versus 58% in WT), an effect associated with coexpression of insulin and glucagon in a fraction of the islet cells in the Ca(V)2.3(-/-) mouse. We propose a specific role for Ca(V)2.3 Ca(2+) channels in second-phase insulin release, that of mediating the Ca(2+) entry needed for replenishment of the releasable pool of granules as well as islet cell differentiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism
  • Calcium Channels / deficiency
  • Calcium Channels / genetics
  • Calcium Channels / metabolism*
  • Calcium Channels, R-Type
  • Cation Transport Proteins / antagonists & inhibitors
  • Cation Transport Proteins / deficiency
  • Cation Transport Proteins / genetics
  • Cation Transport Proteins / metabolism*
  • Cell Differentiation
  • Cells, Cultured
  • Electrophysiology
  • Exocytosis
  • Glucagon / metabolism
  • Glucose / metabolism
  • Glucose / pharmacology
  • Glucose Tolerance Test
  • Homeostasis
  • Immunohistochemistry
  • Insulin / metabolism*
  • Insulin Secretion
  • Islets of Langerhans / cytology
  • Islets of Langerhans / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Pancreatic Hormones / metabolism
  • Patch-Clamp Techniques
  • Perfusion


  • Cacna1e protein, mouse
  • Calcium Channels
  • Calcium Channels, R-Type
  • Cation Transport Proteins
  • Insulin
  • Pancreatic Hormones
  • Glucagon
  • Glucose
  • Calcium