Barker Pi Flush Suppl Rev 5.pdf (254.48 kB)
Download fileXPR1 mediates the pancreatic β-cell phosphate flush
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posted on 2020-09-23, 15:34 authored by Ada AdminAda 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 BerggrenGlucose-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.