A NEW CCK ANALOG DIFFERENTIATES 2 FUNCTIONALLY DISTINCT CCK RECEPTORS IN RAT AND MOUSE PANCREATIC ACINI
A NEW CCK ANALOG DIFFERENTIATES 2 FUNCTIONALLY DISTINCT CCK RECEPTORS IN RAT AND MOUSE PANCREATIC ACINI
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DOI：
10.1152/ajpgi.1989.257.4.g594
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发表时间：
1989-10-01
影响因子：
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通讯作者：
WILLIAMS, JA
中科院分区：
文献类型：
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作者：
MATOZAKI, T;MARTINEZ, J;WILLIAMS, JA
竞争性抑制125 I标记的八肽胆囊收缩素（CCK-8）结合分离的大鼠或小鼠胰腺腺泡的分析表明，在这两个物种CCK-8与两个不同的亲和位点相互作用。一种新合成的CCK类似物在COOH-末端苯丙氨酸残基修饰完全抑制125 I-CCK结合。这种相互作用发生在大鼠腺泡中的单个亲和力位点，但在小鼠腺泡中具有两个不同的亲和力位点。当腺泡孵育浓度增加的CCK-8，淀粉酶释放的双相刺激观察。通过使用大鼠腺泡，类似物刺激淀粉酶的释放，但在超最大浓度下不引起抑制。相比之下，在小鼠胰腺腺泡，类似物显示出类似于CCK-8的淀粉酶释放的双相刺激。CCK-8和类似物刺激[3 H]亮氨酸掺入蛋白质在低浓度下在大鼠胰腺腺泡。较高浓度的CCK-8深刻地抑制[3 H]亮氨酸掺入，而类似物没有抑制作用。此外，在较高浓度的类似物阻断由CCK-8引起的[3 H]亮氨酸掺入的抑制，但不影响氨甲酰胆碱诱导的抑制。然而，在小鼠腺泡中，CCK类似物抑制[3 H]亮氨酸掺入类似于CCK-8的效果。这些结果支持这样的概念，即CCK受体的不同亲和位点或状态的占据与特定的生物学作用相关。CCK受体的模型，提出了两个可互换的亲和状态存在。通过仅以一种状态占据所有受体，新的CCK类似物充当CCK的某些作用的部分激动剂和其它作用的拮抗剂。
Analysis of the competitive inhibition of 125I-labeled cholecystokinin octapeptide (CCK-8) binding to isolated rat or mouse pancreatic acini showed that in both species CCK-8 interacts with two different affinity sites. A newly synthesized CCK analogue modified at the COOH-terminal phenylalanine residue totally inhibited 125I-CCK binding. This interaction occurred with sites of a single affinity in rat acini but with two different affinity sites in mouse acini. When acini were incubated with increasing concentrations of CCK-8, a biphasic stimulation of amylase release was observed. By use of rat acini, the analogs stimulated amylase release but caused no inhibition at supramaximal concentrations. By contrast, in mouse pancreatic acini, analogues showed a biphasic stimulation of amylase release similar to CCK-8. Both CCK-8 and the analogue stimulated [3H]leucine incorporation into protein at low concentrations in rat pancreatic acini. Higher concentrations of CCK-8 profoundly inhibited [3H]leucine incorporation, whereas the analogue had no inhibitory effect. Moreover, the analogue at higher concentrations blocked the inhibition of [3H]leucine incorporation caused by CCK-8 but did not affect carbamylcholine-induced inhibition. In mouse acini, however, the CCK analogue inhibited [3H]leucine incorporation similar to the effect of CCK-8. The results support the concept that occupancy of distinct affinity sites or states of the CCK receptor is associated with specific biological actions. A model of the CCK receptor is proposed in which two interchangeable affinity states exist. By occupying all the receptors in only one state, the new CCK analogues serve as partial agonists of some and antagonists of other actions of CCK.