Barker Pi Flush Suppl Rev 5.pdf (254.48 kB)

XPR1 mediates the pancreatic β-cell phosphate flush

Download (254.48 kB)
figure
posted 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
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.

Funding

This study was supported by the Swedish Research Council, the Novo Nordisk Foundation, Karolinska Institutet, the Swedish Diabetes Association, The Family Knut and Alice Wallenberg Foundation, Diabetes Research and Wellness Foundation, Swedish Foundation for Strategic Research, Berth von Kantzow's Foundation, The Skandia Insurance Company Ltd., Strategic Research Programme in Diabetes at Karolinska Institutet, ERC-2013-AdG 338936-BetaImage, the Stichting af Jochnick Foundation, the Family Erling-Persson Foundation, grants 2010/02272-0, 2014/05214-1 and 2017/11540-7 from FAPESP, grant 301617/2016-3 from CNPq (PQ-1D), grant from STINT and CAPES.

History

Exports