Evidence for two different types of P2 receptors stimulating insulin secretion from pancreatic B cell

1 Adenine nucleotides have been shown to stimulate insulin secretion by acting on P2 receptors of the P2Y type. Since there have been some discrepancies in the insulin response of different analogues of ATP and ADP, we investigated whether two different types of P2 receptors exist on pancreatic B cells. The effects of α,β-methylene ATP, which is more specific for the P2X subtype, were studied in vitro in pancreatic islets and isolated perfused pancreas from rats, in comparison with the potent P2Y receptor agonist ADPβS. 2 In isolated islets, incubated with a slightly stimulating glucose concentration (8.3 mm), α,β-me ATP (200 μm) and ADPβS (50 μm) similarly stimulated insulin secretion; by contrast, under a non stimulating glucose concentration (3 mm), α,β-me ATP was still effective whereas ADPβS was not. In the same way, in islets perifused with 3 mm glucose, α,β-me ATP but not ADPβS induced a partial but significant reduction in the peak 86Rb efflux induced by the ATP-dependent potassium channel opener diazoxide. 3 In the isolated pancreas, perfused with a non stimulating glucose concentration (4.2 mm), ADPβS and α,β-me ATP (5–50 μm), administered for 10 min, induced an immediate, transient and concentration-dependent increase in the insulin secretion; their relative potency was not significantly different. In contrast, with a slightly stimulating glucose concentration (8.3 mm), ADPβS was previously shown to be 100 fold more potent than α,β-me ATP. Furthermore, at 4.2 mm glucose a second administration of α,β-me ATP was ineffective. In the same way, ADPβS was also able to desensitize its own insulin response. At 3 mm glucose, α,β-me ATP as well as ADPβS (50 μm) induced a transient stimulation of insulin secretion and down regulated the action of each other. 4 These results give evidence that pancreatic B cells, in addition to P2Y receptors, which potentiate glucose-induced insulin secretion, are provided with P2X receptors, which transiently stimulate insulin release at low non-stimulating glucose concentration and slightly affect the potassium conductance of the membrane. British Journal of Pharmacology (1998) 125, 1368–1374; doi:10.1038/sj.bjp.0702214