AIMS/HYPOTHESIS: There is evidence that ATP acts as an autocrine signal in beta cells but the receptors and pathways involved are incompletely understood. Here we investigate the receptor subtype(s) and mechanism(s) mediating the effects of ATP on human beta cells. METHODS: We examined the effects of purinergic agonists and antagonists on membrane potential, membrane currents, intracellular Ca(2+) ([Ca(2+)]i) and insulin secretion in human beta cells. RESULTS: Extracellular application of ATP evoked small inward currents (3.4 ± 0.7 pA) accompanied by depolarisation of the membrane potential (by 14.4 ± 2.4 mV) and stimulation of electrical activity at 6 mmol/l glucose. ATP increased [Ca(2+)]i by stimulating Ca(2+) influx and evoking Ca(2+) release via InsP3-receptors in the endoplasmic reticulum (ER). ATP-evoked Ca(2+) release was sufficient to trigger exocytosis in cells voltage-clamped at -70 mV. All effects of ATP were mimicked by the P2Y(1/12/13) agonist ADP and the P2Y1 agonist MRS-2365, whereas the P2X(1/3) agonist α,β-methyleneadenosine-5-triphosphate only had a small effect. The P2Y1 antagonists MRS-2279 and MRS-2500 hyperpolarised glucose-stimulated beta cells and lowered [Ca(2+)]i in the absence of exogenously added ATP and inhibited glucose-induced insulin secretion by 35%. In voltage-clamped cells subjected to action potential-like stimulation, MRS-2279 decreased [Ca(2+)]i and exocytosis without affecting Ca(2+) influx. CONCLUSIONS/ INTERPRETATION: These data demonstrate that ATP acts as a positive autocrine signal in human beta cells by activating P2Y1 receptors, stimulating electrical activity and coupling Ca(2+) influx to Ca(2+) release from ER stores.
AIMS/HYPOTHESIS: There is evidence that ATP acts as an autocrine signal in beta cells but the receptors and pathways involved are incompletely understood. Here we investigate the receptor subtype(s) and mechanism(s) mediating the effects of ATP on human beta cells. METHODS: We examined the effects of purinergic agonists and antagonists on membrane potential, membrane currents, intracellular Ca(2+) ([Ca(2+)]i) and insulin secretion in human beta cells. RESULTS: Extracellular application of ATP evoked small inward currents (3.4 ± 0.7 pA) accompanied by depolarisation of the membrane potential (by 14.4 ± 2.4 mV) and stimulation of electrical activity at 6 mmol/l glucose. ATP increased [Ca(2+)]i by stimulating Ca(2+) influx and evoking Ca(2+) release via InsP3-receptors in the endoplasmic reticulum (ER). ATP-evoked Ca(2+) release was sufficient to trigger exocytosis in cells voltage-clamped at -70 mV. All effects of ATP were mimicked by the P2Y(1/12/13) agonist ADP and the P2Y1 agonist MRS-2365, whereas the P2X(1/3) agonist α,β-methyleneadenosine-5-triphosphate only had a small effect. The P2Y1 antagonists MRS-2279 and MRS-2500 hyperpolarised glucose-stimulated beta cells and lowered [Ca(2+)]i in the absence of exogenously added ATP and inhibited glucose-induced insulin secretion by 35%. In voltage-clamped cells subjected to action potential-like stimulation, MRS-2279 decreased [Ca(2+)]i and exocytosis without affecting Ca(2+) influx. CONCLUSIONS/ INTERPRETATION: These data demonstrate that ATP acts as a positive autocrine signal in human beta cells by activating P2Y1 receptors, stimulating electrical activity and coupling Ca(2+) influx to Ca(2+) release from ER stores.
Authors: M Caroline Jacques-Silva; Mayrin Correa-Medina; Over Cabrera; Rayner Rodriguez-Diaz; Natalia Makeeva; Alberto Fachado; Juan Diez; Dora M Berman; Norma S Kenyon; Camillo Ricordi; Antonello Pileggi; R Damaris Molano; Per-Olof Berggren; Alejandro Caicedo Journal: Proc Natl Acad Sci U S A Date: 2010-03-22 Impact factor: 11.205
Authors: Amélia M Silva; Ricardo J Rodrigues; Angelo R Tomé; Rodrigo A Cunha; Stanley Misler; Luís M Rosário; Rosa M Santos Journal: Pancreas Date: 2008-04 Impact factor: 3.327
Authors: Matthias Braun; Reshma Ramracheya; Martin Bengtsson; Quan Zhang; Jovita Karanauskaite; Chris Partridge; Paul R Johnson; Patrik Rorsman Journal: Diabetes Date: 2008-04-04 Impact factor: 9.461
Authors: Hak Sung Kim; Michihiro Ohno; Bin Xu; Hea Ok Kim; Yongseok Choi; Xiao D Ji; Savitri Maddileti; Victor E Marquez; T Kendall Harden; Kenneth A Jacobson Journal: J Med Chem Date: 2003-11-06 Impact factor: 7.446
Authors: Diane C Saunders; Marcela Brissova; Neil Phillips; Shristi Shrestha; John T Walker; Radhika Aramandla; Greg Poffenberger; David K Flaherty; Kevin P Weller; Julie Pelletier; Tracy Cooper; Matt T Goff; John Virostko; Alena Shostak; E Danielle Dean; Dale L Greiner; Leonard D Shultz; Nripesh Prasad; Shawn E Levy; Robert H Carnahan; Chunhua Dai; Jean Sévigny; Alvin C Powers Journal: Cell Metab Date: 2018-11-15 Impact factor: 27.287
Authors: Jonathan R Weitz; Carol Jacques-Silva; Mirza Muhammed Fahd Qadir; Oliver Umland; Elizabeth Pereira; Farhan Qureshi; Alejandro Tamayo; Juan Dominguez-Bendala; Rayner Rodriguez-Diaz; Joana Almaça; Alejandro Caicedo Journal: Diabetes Date: 2020-04-03 Impact factor: 9.461
Authors: Rafael Arrojo e Drigo; Yusuf Ali; Juan Diez; Dinesh Kumar Srinivasan; Per-Olof Berggren; Bernhard O Boehm Journal: Diabetologia Date: 2015-07-28 Impact factor: 10.122
Authors: Cita Bauer; Julia Kaiser; Jelena Sikimic; Peter Krippeit-Drews; Martina Düfer; Gisela Drews Journal: Endocrine Date: 2018-09-18 Impact factor: 3.633