XPR1 mediates the pancreatic β-cell phosphate flush
figureposted on 23.09.2020 by Ada Admin, Christopher J. Barker, Fernando Henrique Galvão Tessaro, Sabrina de Souza Ferreira, Rafael Simas, Thais S. Ayala, Martin Köhler, Subu Surendran Rajasekaran, Joilson O. Martins, Elisabetta Darè, Per Olof Berggren
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Glucose-stimulated insulin secretion is the hallmark of the pancreatic β-cell, a critical player in the regulation of blood glucose concentration. In 1974 Dawson, Freinkel and co-workers made the remarkable observation that an efflux of intracellular inorganic phosphate (Pi) accompanied the events of stimulated insulin secretion. The mechanism behind this ‘phosphate flush’, its association with insulin secretion and its regulation have since then remained a mystery. We recapitulated the phosphate flush in the MIN6m9 β-cell line and pseudoislets. We demonstrated that knockdown of XPR1, a phosphate transporter present in MIN6m9 cells and pancreatic islets, prevented this flush. Concomitantly, XPR1 silencing led to intracellular Pi accumulation and a potential impact on Ca2+ signaling. XPR1 knockdown slightly blunted first phase glucose-stimulated insulin secretion in MIN6m9 cells, but had no significant impact on pseudoislet secretion. In keeping with other cell types, basal Pi efflux was stimulated by inositol pyrophosphates and basal intracellular Pi accumulated following knockdown of inositol hexakisphosphate kinases. However, the glucose-driven phosphate flush occurred despite inositol pyrophosphate depletion. Finally, whilst it is unlikely that XPR1 directly affects exocytosis, it may protect Ca2+ signaling. Thus we have revealed XPR1 as the missing mediator of the phosphate flush, shedding light on a 45-year-old mystery.