XPR1 Mediates the Pancreatic beta-Cell Phosphate Flush

Autor(es)

Barker, Christopher J. ^[1] ; Tessaro, Fernando Henrique Galvao ^{[1, 2]} ; Ferreira, Sabrina de Souza ^{[1, 2]} ; Simas, Rafael ^[1] ; Ayala, Thais S. ^{[1, 2]} ; Kohler, Martin ^[1] ; Rajasekaran, Subu Surendran ^[1] ; Martins, Joilson O. ^[2] ; Dare, Elisabetta ^[1] ; Berggren, Per-Olof ^[1]

Afiliação do(s) autor(es)

^[1] Karolinska Inst, Rolf Luft Res Ctr Diabet & Endocrinol, Stockholm - Sweden

^[2] Univ Sao Paulo, Sch Pharmaceut Sci, Dept Clin & Toxicol Anal, Lab Immunoendocrinol, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Diabetes; v. 70, n. 1, p. 111-118, JAN 2021.
• Citações Web of Science: 1

Resumo

Glucose-stimulated insulin secretion is the hallmark of the pancreatic beta-cell, a critical player in the regulation of blood glucose concentration. In 1974, the remarkable observation was made that an efflux of intracellular inorganic phosphate (P-i) 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 beta-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 P-i 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 P-i efflux was stimulated by inositol pyrophosphates, and basal intracellular P-i accumulated following knockdown of inositol hexakisphosphate kinases. However, the glucose-driven phosphate flush occurred despite inositol pyrophosphate depletion. Finally, while 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. (AU)

• Processo FAPESP: 14/05214-1 - Investigando o papel da insulina em diferentes infecções em animais diabéticos e sadios
• Beneficiário: Joilson de Oliveira Martins
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 10/02272-0 - Efeito da insulina na inflamação pulmonar secundária a sepse, na imunidade inata, na ativação do seu gene (BGK) e seus receptores (IR-A e IR-B)
• Beneficiário: Joilson de Oliveira Martins
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores
• Processo FAPESP: 17/11540-7 - Investigando o papel da insulina na vigência da inflamação alérgica pulmonar em camundongos diabéticos e sadios
• Beneficiário: Joilson de Oliveira Martins
• Modalidade de apoio: Auxílio à Pesquisa - Regular