Somatostatin receptor type 5 modulates somatostatin receptor type 2 regulation of adrenocorticotropin secretion
Somatostatin receptor type 5 modulates somatostatin receptor type 2 regulation of adrenocorticotropin secretion
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DOI：
10.1074/jbc.m501998200
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发表时间：
2005-06-24
影响因子：
4.8
通讯作者：
Melmed, S
中科院分区：
文献类型：
--
作者：
Ben-Shlomo, A;Wawrowsky, KA;Melmed, S
生长抑素抑制垂体瘤细胞促肾上腺皮质激素（ACTH）分泌。为了评估生长抑素受体亚型5（SST 5）对生长抑素受体亚型2（SST 2）在这些细胞中的作用，我们评估了对新型高度单受体选择性肽激动剂和多受体激动剂（包括奥曲肽和生长抑素-28）的多途径反应。奥曲肽和生长抑素-28细胞膜结合亲和力与其各自的SST 2-选择性肽配体相关。虽然奥曲肽与SST 2选择性激动剂对cAMP蓄积和ACTH分泌具有相似的抑制效力（皮摩尔），但生长抑素-28表现出更高的效力（飞摩尔）。通过荧光共聚焦显微镜评估的基线自发钙振荡揭示了两种不同的效应：SST 2激活减少了在飞摩尔浓度下的振荡，这反映在平均归一化振荡幅度的高抑制效力上，而SST 5激活诱导短暂的振荡暂停和增加的振荡幅度。奥曲肽表现出两种受体的综合效应;然而，生长抑素-28表现出两种单独抑制效力的复杂反应。SST 2的内化可视化与SST 2选择性激动剂在较低的浓度比奥曲肽或生长抑素-28，而SST 5没有内化。使用单受体选择性肽激动剂，结果表明，在AtT-20细胞中，SST 5调节占主导地位的SST 2行动，减弱SST 2对细胞内钙振荡和内化的影响。这可能解释了生长抑素28的上级效力，并为生长抑素配体设计治疗ACTH分泌型垂体瘤提供了理论基础。
Somatostatin inhibits adrenocorticotropin ( ACTH) secretion from pituitary tumor cells. To assess the contribution of somatostatin receptor subtype 5 (SST5) to somatostatin receptor subtype 2 ( SST2) action in these cells, we assessed multipathway responses to novel highly monoreceptor-selective peptide agonists and multireceptor agonists, including octreotide and somatostatin-28. Octreotide and somatostatin-28 cell membrane binding affinities correlated with their respective SST2-selective peptide ligand. Although octreotide had similar inhibiting potency (picomolar) for cAMP accumulation and ACTH secretion as an SST2-selective agonist, somatostatin-28 exhibited a higher potency (femtomolar). Baseline spontaneous calcium oscillations assessed by fluorescent confocal microscopy revealed two distinct effects: SST2 activation reduced oscillations at femtomolar concentrations reflected by high inhibiting potency of averaged normalized oscillation amplitude, whereas SST5 activation induces brief oscillation pauses and increased oscillation amplitude. Octreotide exhibits an integrated effect of both receptors; however, somatostatin-28 exhibited a complex response with two separate inhibitory potencies. SST2 internalization was visualized with SST2-selective agonist at lower concentrations than for octreotide or somatostatin-28, whereas SST5 did not internalize. Using monoreceptor-selective peptide agonists, the results indicate that, in AtT-20 cells, SST5 regulates the dominant SST2 action, attenuating SST2 effects on intracellular calcium oscillation and internalization. This may explain superior somatostatin-28 potency and provides a rationale for somatostatin ligand design to treat ACTH-secreting pituitary tumors.