CaV2.3 calcium channels control second-phase insulin release.
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.
Jing
Xingjun
X
Diabetes Programme at Lund University, Lund, Sweden.
Li
Dai-Qing
DQ
Olofsson
Charlotta S
CS
Salehi
Albert
A
Surve
Vikas V
VV
Caballero
José
J
Ivarsson
Rosita
R
Lundquist
Ingmar
I
Pereverzev
Alexey
A
Schneider
Toni
T
Rorsman
Patrik
P
Renström
Erik
E
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
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