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

Abstract

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.

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