期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 107, 期 14, 页码 6465-6470出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0908935107
关键词
extracellular ATP; human pancreatic beta cell; insulin secretion; P2X receptor; positive autocrine feedback
资金
- National Institutes of Health Grants for General Clinical Research Center [M01RR16587, 1R01-DK55347-IU42RR016603]
- Islet Cell Resources [5U42RR016603, 1R03DK075487-01]
- Juvenile Diabetes Research Foundation International [4-2004-361, 3-2006-853]
- Diabetes Research Institute Foundation
- Swedish Research Council, Novo Nordisk Foundation
- Swedish Diabetes Association
- Berth von Kantzow's Foundation
- Family Erling-Persson Foundation
- Comissao de Aperfeicoamento de Pessoal de Nivel Superior/Brazil
Extracellular ATP has been proposed as a paracrine signal in rodent islets, but it is unclear what role ATP plays in human islets. We now show the presence of an ATP signaling pathway that enhances the human beta cell's sensitivity and responsiveness to glucose fluctuations. By using in situ hybridization, RT-PCR, immunohistochemistry, and Western blotting as well as recordings of cytoplasmic-free Ca2+ concentration, [Ca2+](i), and hormone release in vitro, we show that human beta cells express ionotropic ATP receptors of the P2X(3) type and that activation of these receptors by ATP coreleased with insulin amplifies glucose-induced insulin secretion. Released ATP activates P2X(3) receptors in the beta-cell plasma membrane, resulting in increased [Ca2+](i) and enhanced insulin secretion. Therefore, in human islets, released ATP forms a positive autocrine feedback loop that sensitizes the beta cell's secretory machinery. This may explain how the human pancreatic beta cell can respond so effectively to relatively modest changes in glucose concentration under physiological conditions in vivo.
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