title: CaV2.3 calcium channels control second-phase insulin release.
abstract: 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.
authors.affiliation: Diabetes Programme at Lund University, Lund, Sweden.
authors.forename: Xingjun
authors.initials: X
authors.lastname: Jing
authors.forename: Dai-Qing
authors.initials: DQ
authors.lastname: Li
authors.forename: Charlotta S
authors.initials: CS
authors.lastname: Olofsson
authors.forename: Albert
authors.initials: A
authors.lastname: Salehi
authors.forename: Vikas V
authors.initials: VV
authors.lastname: Surve
authors.forename: José
authors.initials: J
authors.lastname: Caballero
authors.forename: Rosita
authors.initials: R
authors.lastname: Ivarsson
authors.forename: Ingmar
authors.initials: I
authors.lastname: Lundquist
authors.forename: Alexey
authors.initials: A
authors.lastname: Pereverzev
authors.forename: Toni
authors.initials: T
authors.lastname: Schneider
authors.forename: Patrik
authors.initials: P
authors.lastname: Rorsman
authors.forename: Erik
authors.initials: E
authors.lastname: Renström
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020908:Calcium Channels, R-Type; D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D002478:Cells, Cultured; D004594:Electrophysiology; D005089:Exocytosis; D005934:Glucagon / Q000378:metabolism; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D005951:Glucose Tolerance Test; D006706:Homeostasis; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010187:Pancreatic Hormones / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010477:Perfusion
chemical_list: C498916:Cacna1e protein, mouse; D015220:Calcium Channels; D020908:Calcium Channels, R-Type; D027682:Cation Transport Proteins; D007328:Insulin; D010187:Pancreatic Hormones; D005934:Glucagon; D005947:Glucose; D002118:Calcium