Extracellular Adenosine 5′-Triphosphate Modulates Insulin Secretion via Functionally Active Purinergic Receptors of X and Y Subtype

Extracellular nucleotides modulate several cell functions via specific receptors, P2X and P2Y. We explored the differential role of these receptors in the control of insulin secretion (InSec). In INS-1e cells grown in 11 mm glucose and then acutely exposed to 3.3, 7.5, 11, or 20 mm, coincubation with ATP, the global agonist of both P2X and P2Y receptors, induced a dose-dependent (P < 0.0001) reduction in insulin release (P < 0.0001) that was more marked at higher glucose concentrations (P < 0.0001 for the interaction). This effect was fully prevented (P < 0.0001) by incubating ATP-treated cells in the presence of apyrase, an ecto-ATP/ADPase. Uridine 5′-triphosphate (UTP), preferential agonist of P2Y receptors, significantly stimulated InSec at all glucose concentrations tested, whereas benzoyl-benzoyl ATP (BzATP), a strong and highly selective P2X7 agonist, did not influence InSec. Oxidized ATP, which completely suppresses P2X activity, abolished the inhibitory effect of ATP on InSec. Similar results were...