Petit P, Hillaire-Buys D, Manteghetti M, Debrus S, Chapal J, Loubatières-Mariani M M
Laboratoire de Pharmacologie (UPRES EA 1677), Faculté de Médecine, Université Montpellier I, France.
Br J Pharmacol. 1998 Nov;125(6):1368-74. doi: 10.1038/sj.bjp.0702214.
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 alpha,beta-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 ADPbetaS. In isolated islets, incubated with a slightly stimulating glucose concentration (8.3 mM), alpha,beta-me ATP (200 microM) and ADPbetaS (50 microM) similarly stimulated insulin secretion; by contrast, under a non stimulating glucose concentration (3 mM), alpha,beta-me ATP was still effective whereas ADPbetaS was not. In the same way, in islets perifused with 3 mM glucose, alpha,beta-me ATP but not ADPbetaS induced a partial but significant reduction in the peak 86Rb efflux induced by the ATP-dependent potassium channel opener diazoxide. In the isolated pancreas, perfused with a non stimulating glucose concentration (4.2 mM), ADPbetaS and alpha,beta-me ATP (5-50 microM), 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), ADPbetaS was previously shown to be 100 fold more potent than alpha,beta-me ATP. Furthermore, at 4.2 mM glucose a second administration of alpha,beta-me ATP was ineffective. In the same way, ADPbetaS was also able to desensitize its own insulin response. At 3 mM glucose, alpha,beta-me ATP as well as ADPbetaS (50 microM) induced a transient stimulation of insulin secretion and down regulated the action of each other. 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.
腺嘌呤核苷酸已被证明可通过作用于P2Y型P2受体来刺激胰岛素分泌。由于不同的ATP和ADP类似物在胰岛素反应方面存在一些差异，我们研究了胰腺β细胞上是否存在两种不同类型的P2受体。与强效P2Y受体激动剂ADPβS相比，在体外对大鼠胰岛和分离的灌注胰腺研究了对P2X亚型更具特异性的α,β-亚甲基ATP的作用。在与轻微刺激葡萄糖浓度（8.3 mM）孵育的分离胰岛中，α,β-亚甲基ATP（200 μM）和ADPβS（50 μM）同样刺激胰岛素分泌；相比之下，在非刺激葡萄糖浓度（3 mM）下，α,β-亚甲基ATP仍然有效，而ADPβS则无效。同样，在以3 mM葡萄糖灌注的胰岛中，α,β-亚甲基ATP而非ADPβS诱导由ATP依赖性钾通道开放剂二氮嗪诱导的峰值86Rb外流部分但显著降低。在以非刺激葡萄糖浓度（4.2 mM）灌注的分离胰腺中，给予10分钟的ADPβS和α,β-亚甲基ATP（5 - 50 μM）诱导胰岛素分泌立即、短暂且浓度依赖性增加；它们的相对效力没有显著差异。相比之下，在轻微刺激葡萄糖浓度（8.3 mM）下，先前显示ADPβS的效力比α,β-亚甲基ATP高100倍。此外，在4.2 mM葡萄糖时，第二次给予α,β-亚甲基ATP无效。同样，ADPβS也能够使其自身的胰岛素反应脱敏。在3 mM葡萄糖时，α,β-亚甲基ATP以及ADPβS（50 μM）诱导胰岛素分泌的短暂刺激并下调彼此的作用。这些结果表明，胰腺β细胞除了具有增强葡萄糖诱导胰岛素分泌的P2Y受体外，还具有P2X受体，后者在低非刺激葡萄糖浓度下短暂刺激胰岛素释放并轻微影响膜的钾电导。
