Ren Song-Guang, Taylor John, Dong Jesse, Yu Run, Culler Michael D, Melmed Shlomo
Cedars-Sinai Research Institute, University of California, Los Angeles, School of Medicine, Los Angeles, California 90048, USA.
J Clin Endocrinol Metab. 2003 Sep;88(9):4239-45. doi: 10.1210/jc.2003-030303.
We previously demonstrated that somatostatin (SRIF)-induced inhibition of GH secretion from human pituitary cells is mediated through both the SRIF receptor (SSTR) 2 and 5 subtypes. The interplay between these two SSTR subtypes in regulating GH was therefore tested in primary human fetal pituitary cultures (18-30 wk gestation). GHRH (10 nM)-stimulated GH secretion (51% increase, P < 0.05) was suppressed equally by either SSTR2 or SSTR5-selective agonists (10 nM). GH suppression correlated with agonist affinity for their respective receptor subtypes. Combined addition of SSTR2- and SSTR5-specific agonists was synergistic for GH suppression, achieving 73% (P < 0.05) inhibition as compared with inhibition attained with SSTR2 (32%) and SSTR5 (34%) agonists used alone (P < 0.05). The SSTR2 selective antagonist BIM-23454 dose-dependently blocked SSTR2 but not SSTR5-induced suppression of GH secretion. BIM-23454 also completely reversed GH suppression in response to the combined activation of SSTR2 and SSTR5. The IC(50) for BIM-23454 reversal of agonist-induced GH suppression was 55 nM and 33 nM for two SSTR2 agonists, 45 nM and 40 nM for the combination of SSTR2 and SSTR5 agonists, respectively, and 45 nM for the SSTR2/SSTR5 agonist BIM-23244, all of which were similar to the affinity of BIM-23454 for SSTR2 (32 nM). These results suggest the following: 1) activation of both SSTR2 and SSTR5 induces a functional association of receptor subtypes, resulting in synergistic GH suppression; 2) BIM-23454 is a potent SSTR2-selective antagonist capable of reversing SRIF-induced GH suppression; and 3) the ability of a selective SSTR2 antagonist to inhibit the GH suppressing action of SSTR2 agonist alone, SSTR2/SSTR5 biselective agonists, or SSTR2 and SSTR5 agonists in combination support the concept of a functional interaction between somatotroph SSTR2 and SSTR5 subtypes in primary human fetal pituitary cells.
我们之前证实，生长抑素（SRIF）诱导的人垂体细胞生长激素（GH）分泌抑制是通过SRIF受体（SSTR）2和5亚型介导的。因此，在原代人胎儿垂体培养物（妊娠18 - 30周）中测试了这两种SSTR亚型在调节GH方面的相互作用。生长激素释放激素（GHRH，10 nM）刺激的GH分泌（增加51%，P < 0.05）被SSTR2或SSTR5选择性激动剂（10 nM）同等程度地抑制。GH抑制与激动剂对其各自受体亚型的亲和力相关。联合添加SSTR2和SSTR5特异性激动剂对GH抑制具有协同作用，与单独使用SSTR2激动剂（32%）和SSTR5激动剂（34%）相比，实现了73%的抑制（P < 0.05）。SSTR2选择性拮抗剂BIM - 23454剂量依赖性地阻断SSTR2诱导的而非SSTR5诱导的GH分泌抑制。BIM - 23454还完全逆转了因SSTR2和SSTR5联合激活而导致的GH抑制。对于两种SSTR2激动剂，BIM - 23454逆转激动剂诱导的GH抑制的半数抑制浓度（IC50）分别为55 nM和33 nM；对于SSTR2和SSTR5激动剂组合，IC50分别为45 nM和40 nM；对于SSTR2/SSTR5激动剂BIM - 23244，IC50为45 nM，所有这些均与BIM - 23454对SSTR2的亲和力（32 nM）相似。这些结果表明：1）SSTR2和SSTR5的激活均诱导受体亚型的功能关联，导致对GH的协同抑制；2）BIM - 23454是一种有效的SSTR2选择性拮抗剂，能够逆转SRIF诱导的GH抑制；3）选择性SSTR2拮抗剂抑制单独的SSTR2激动剂、SSTR2/SSTR5双选择性激动剂或SSTR2和SSTR5激动剂组合的GH抑制作用的能力，支持了在原代人胎儿垂体细胞中生长激素细胞SSTR2和SSTR5亚型之间存在功能相互作用的概念。
