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lüll Mechanisms of control of the free Ca2+ concentration in the endoplasmic reticulum of mouse pancreatic beta-cells: interplay with cell metabolism and Ca2+ c and role of SERCA2b and SERCA3 Ravier MA; Daro D; Roma LP; Jonas JC; Cheng-Xue R; Schuit FC; Gilon PDiabetes 2011[Oct]; 60 (10): 2533-45OBJECTIVE: Sarco-endoplasmic reticulum Ca(2+)-ATPase 2b (SERCA2b) and SERCA3 pump Ca(2+) in the endoplasmic reticulum (ER) of pancreatic beta-cells. We studied their role in the control of the free ER Ca(2+) concentration ([Ca(2+)](ER)) and the role of SERCA3 in the control of insulin secretion and ER stress. RESEARCH DESIGN AND METHODS: beta-Cell [Ca(2+)](ER) of SERCA3(+/+) and SERCA3(-/-) mice was monitored with an adenovirus encoding the low Ca(2+)-affinity sensor D4 addressed to the ER (D4ER) under the control of the insulin promoter. Free cytosolic Ca(2+) concentration ([Ca(2+)](c)) and [Ca(2+)](ER) were simultaneously recorded. Insulin secretion and mRNA levels of ER stress genes were studied. RESULTS: Glucose elicited synchronized [Ca(2+)](ER) and [Ca(2+)](c) oscillations. [Ca(2+)](ER) oscillations were smaller in SERCA3(-/-) than in SERCA3(+/+) beta-cells. Stimulating cell metabolism with various [glucose] in the presence of diazoxide induced a similar dose-dependent [Ca(2+)](ER) rise in SERCA3(+/+) and SERCA3(-/-) beta-cells. In a Ca(2+)-free medium, glucose moderately raised [Ca(2+)](ER) from a highly buffered cytosolic Ca(2+) pool. Increasing [Ca(2+)](c) with high [K] elicited a [Ca(2+)](ER) rise that was larger but more transient in SERCA3(+/+) than SERCA3(-/-) beta-cells because of the activation of a Ca(2+) release from the ER in SERCA3(+/+) beta-cells. Glucose-induced insulin release was larger in SERCA3(-/-) than SERCA3(+/+) islets. SERCA3 ablation did not induce ER stress. CONCLUSIONS: [Ca(2+)](c) and [Ca(2+)](ER) oscillate in phase in response to glucose. Upon [Ca(2+)](c) increase, Ca(2+) is taken up by SERCA2b and SERCA3. Strong Ca(2+) influx triggers a Ca(2+) release from the ER that depends on SERCA3. SERCA3 deficiency neither impairs Ca(2+) uptake by the ER upon cell metabolism acceleration and insulin release nor induces ER stress.|Animals[MESH]|Calcium/*metabolism/pharmacology[MESH]|Diazoxide/pharmacology[MESH]|Endoplasmic Reticulum/metabolism[MESH]|Gene Deletion[MESH]|Gene Expression Regulation[MESH]|Genetic Engineering[MESH]|Glucose/pharmacology[MESH]|Insulin-Secreting Cells/drug effects/*metabolism[MESH]|Insulin/genetics/metabolism[MESH]|Mice[MESH]|Mice, Knockout[MESH]|Promoter Regions, Genetic[MESH]|Sarcoplasmic Reticulum Calcium-Transporting ATPases/genetics/*metabolism[MESH]|Vasodilator Agents/pharmacology[MESH] |