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Role for Plasma Membrane-Related Ca²⁺-ATPase-1 (ATP2C1) in Pancreatic ß-Cell Ca²⁺ Homeostasis Revealed by RNA Silencing

From the Henry Wellcome Laboratories of Integrated Cell Signaling and Department of Biochemistry, School of Medical Sciences, University Walk, University of Bristol, Bristol, U.K

Changes in intracellular Ca²⁺ concentration play a key role in the regulation of insulin secretion by glucose and other secretagogues. Here, we explore the importance of the secretory pathway Ca²⁺-ATPase, plasma membrane-related Ca²⁺-ATPase-1 (PMR1; human orthologue ATP2C1) in intracellular Ca²⁺ homeostasis in pancreatic islet ß-cells. Endogenous PMR1 mRNA and protein were detected in both isolated rat islets and ß-cell-derived lines (MIN6 and INS1). Subcellular fractionation of the cell lines revealed PMR1 immunoreactivity in both microsomal and dense-core secretory vesicle-enriched fractions. Correspondingly, depletion of cellular PMR1 with small interfering RNAs inhibited Ca²⁺ uptake into the endoplasmic reticulum and secretory vesicles by 20%, as assessed using organelle-targeted aequorins in permeabilized INS1 cells. In intact cells, PMR1 depletion markedly enhanced flux though L-type Ca²⁺ channels and augmented glucose-stimulated, but not basal, insulin secretion. Whereas average cytosolic [Ca²⁺] increases in response to 30.0 mmol/l glucose were unaffected by PMR1 depletion, [Ca²⁺] oscillation shape, duration, and decay rate in response to glucose plus tetraethylammonium were modified in PMR1-depleted single cells, imaged using fluo-3-acetoxymethylester. PMR1 thus plays an important role, which is at least partially nonoverlapping with that of sarco(endo-)plasmic reticulum Ca²⁺-ATPases, in the control of ß-cell Ca²⁺ homeostasis and insulin secretion.

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