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SERCA3 Ablation Does Not Impair Insulin Secretion but Suggests Distinct Roles of Different Sarcoendoplasmic Reticulum Ca²⁺ Pumps for Ca²⁺ Homeostasis in Pancreatic ß-cells

¹ Unité d’Endocrinologie et Métabolisme, University of Louvain Faculty of Medicine, Brussels, Belgium
² Unité d’Anatomie Pathologique Spéciale, University of Louvain Faculty of Medicine, Brussels, Belgium
³ Department of Molecular Genetics, University of Cincinnati College of Medicine, Cincinnati, Ohio
⁴ Laboratorium voor Fysiologie, Katholieke Universiteit Leuven, Leuven, Belgium

Two sarcoendoplasmic reticulum Ca²⁺-ATPases, SERCA3 and SERCA2b, are expressed in pancreatic islets. Immunocytochemistry showed that SERCA3 is restricted to ß-cells in the mouse pancreas. Control and SERCA3-deficient mice were used to evaluate the role of SERCA3 in ß-cell cytosolic-free Ca²⁺ concentration ([Ca²⁺]_c) regulation, insulin secretion, and glucose homeostasis. Basal [Ca²⁺]_c was not increased by SERCA3 ablation. Stimulation with glucose induced a transient drop in basal [Ca²⁺]_c that was suppressed by inhibition of all SERCAs with thapsigargin (TG) but unaffected by selective SERCA3 ablation. Ca²⁺ mobilization by acetylcholine was normal in SERCA3-deficient ß-cells. In contrast, [Ca²⁺]_c oscillations resulting from intermittent glucose-stimulated Ca²⁺ influx and [Ca²⁺]_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 Ca²⁺ 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 [Ca²⁺]_c regulation in ß-cells. SERCA3 becomes operative when [Ca²⁺]_c rises and is required for normal [Ca²⁺]_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.

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