ATP mediates a negative autocrine signal on stimulus-secretion coupling in mouse pancreatic β-cells.

PURPOSE: The role of ATP, which is secreted by pancreatic β-cells, is still a matter of debate. It has been postulated that extracellular ATP acts as a positive auto- or paracrine signal in β-cells amplifying insulin secretion. However, there is rising evidence that extracellular ATP may also mediate a negative signal.

METHODS: We evaluated whether extracellular ATP interferes with the Ca2+ -mediated negative feedback mechanism that regulates oscillatory activity of β-cells.

RESULTS: To experimentally uncover the Ca2+ -induced feedback we applied a high extracellular Ca2+ concentration. Under this condition ATP (100 µM) inhibited glucose-evoked oscillations of electrical activity and hyperpolarized the membrane potential. Furthermore, ATP acutely increased the interburst phase of Ca2+ oscillations and reduced the current through L-type Ca2+ channels. Accordingly, ATP (500 µM) decreased glucose-induced insulin secretion. The ATP effect was not mimicked by AMP, ADP, or adenosine. The use of specific agonists and antagonists and mice deficient of large conductance Ca2+ -dependent K+ channels revealed that P2X, but not P2Y receptors, and Ca2+ -dependent K+ channels are involved in the underlying signaling cascade induced by ATP. The effectiveness of ATP to interfere with parameters of stimulus-secretion coupling is markedly reduced at low extracellular Ca2+ concentration.

CONCLUSION: It is suggested that extracellular ATP which is co-secreted with insulin in a pulsatile manner during glucose-stimulated exocytosis provides a negative feedback signal driving β-cell oscillations in co-operation with Ca2+ and other signals.