SERCA3 ablation does not impair insulin secretion but suggests distinct roles of different sarcoendoplasmic reticulum Ca(2+) pumps for Ca(2+) homeostasis in pancreatic beta-cells.
Two sarcoendoplasmic reticulum Ca(2+)-ATPases, SERCA3 and SERCA2b, are expressed in pancreatic islets. Immunocytochemistry showed that SERCA3 is restricted to beta-cells in the mouse pancreas. Control and SERCA3-deficient mice were used to evaluate the role of SERCA3 in beta-cell cytosolic-free Ca(2+) concentration ([Ca(2+)](c)) regulation, insulin secretion, and glucose homeostasis. Basal [Ca(2+)](c) was not increased by SERCA3 ablation. Stimulation with glucose induced a transient drop in basal [Ca(2+)](c) that was suppressed by inhibition of all SERCAs with thapsigargin (TG) but unaffected by selective SERCA3 ablation. Ca(2+) mobilization by acetylcholine was normal in SERCA3-deficient beta-cells. In contrast, [Ca(2+)](c) oscillations resulting from intermittent glucose-stimulated Ca(2+) influx and [Ca(2+)](c) transients induced by pulses of high K(+) were similarly affected by SERCA3 ablation or TG pretreatment of control islets; their amplitude was increased and their slow descending phase suppressed. This suggests that, during the decay of each oscillation, the endoplasmic reticulum releases Ca(2+) that was pumped by SERCA3 during the upstroke phase. SERCA3 ablation increased the insulin response of islets to 15 mmol/l glucose. However, basal and postprandial plasma glucose and insulin concentrations in SERCA3-deficient mice were normal. In conclusion, SERCA2b, but not SERCA3, is involved in basal [Ca(2+)](c) regulation in beta-cells. SERCA3 becomes operative when [Ca(2+)](c) rises and is required for normal [Ca(2+)](c) oscillations in response to glucose. However, a lack of SERCA3 is insufficient in itself to alter glucose homeostasis or impair insulin secretion in mice.
Arredouani
Abdelilah
A
Unité d'Endocrinologie et Métabolisme, University of Louvain Faculty of Medicine, Brussels, Belgium.
Guiot
Yves
Y
Jonas
Jean-Christophe
JC
Liu
Lynne H
LH
Nenquin
Myriam
M
Pertusa
José A
JA
Rahier
Jacques
J
Rolland
Jean-François
JF
Shull
Gary E
GE
Stevens
Martine
M
Wuytack
Frank
F
Henquin
Jean-Claude
JC
Gilon
Patrick
P
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology; D000252:Calcium-Transporting ATPases / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism*; D005091:Exons; D005947:Glucose / Q000502:physiology; D006706:Homeostasis; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000166:cytology / Q000201:enzymology / Q000502:physiology*; D007527:Isoenzymes / Q000235:genetics; D007700:Kinetics; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D013997:Time Factors
D007328:Insulin; D007527:Isoenzymes; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506950:Atp2a3 protein, mouse; D000252:Calcium-Transporting ATPases; D005947:Glucose; D002118:Calcium