Shimon I, Taylor J E, Dong J Z, Bitonte R A, Kim S, Morgan B, Coy D H, Culler M D, Melmed S
Department of Medicine, Cedars-Sinai Research Institute, University of California, Los Angeles School of Medicine 90048, USA.
J Clin Invest. 1997 Feb 15;99(4):789-98. doi: 10.1172/JCI119225.
Somatostatin (SRIF), a hypothalamic inhibitor of pituitary growth hormone (GH) and thyroid-stimulating hormone (TSH) secretion, binds to five distinct receptor (SSTR) subtypes. We therefore tested SSTR subtype-specific SRIF analogs in primary human fetal pituitary cultures (23-25-wk gestation) to elucidate their role in regulating human pituitary function. Using reverse transcription-PCR, mRNA expression of SSTR2 and SSTR5 were detected in fetal pituitary by 25 wk. SRIF analog affinities were determined by membrane radioligand binding in cells stably expressing the human SSTR forms. GH secretion was suppressed equally (40-60%, P < 0.005) by analogs preferential for either SSTR2 (IC50 for receptor binding affinity, 0.19-0.42 nM) or SSTR5 (IC50, 0.37 nM), and compounds with enhanced affinity for SSTR2 were more potent (EC50 for GH suppression, 0.05-0.09 nM) than Lanreotide (EC50, 2.30 nM) and SRIF (EC50, 0.19 nM). Similarly, analogs with high affinity for SSTR2 or SSTR5 decreased TSH secretion (30-40%, P < 0.005). However, prolactin was effectively inhibited only by compounds preferentially bound to SSTR2 (20-30%, P < 0.05). Luteinizing hormone was modestly decreased (15-20%) by SSTR2- or SSTR5-specific analogs. An SSTR5-specific analog also exclusively inhibited GH in acromegalic tumor cells. Thus, SRIF regulation of GH and TSH in primary human fetal pituitary cells is mediated by both SSTR2 and SSTR5, both of which are abundantly expressed by 25 wk. In contrast, suppression of prolactin is mediated mainly by SSTR2. These results indicate that SSTR5 is critical for physiologic regulation of GH and TSH. SRIF analogs with selective affinity for this receptor may therefore be more effective in the treatment of hormone-secreting pituitary adenomas.
生长抑素（SRIF）是一种下丘脑分泌的抑制垂体生长激素（GH）和促甲状腺激素（TSH）分泌的物质，它可与五种不同的受体（SSTR）亚型结合。因此，我们在原代人胎儿垂体培养物（妊娠23 - 25周）中测试了SSTR亚型特异性的SRIF类似物，以阐明它们在调节人垂体功能中的作用。通过逆转录 - PCR，在25周时检测到胎儿垂体中SSTR2和SSTR5的mRNA表达。通过膜放射配体结合法在稳定表达人SSTR形式的细胞中测定SRIF类似物的亲和力。对SSTR2（受体结合亲和力的IC50为0.19 - 0.42 nM）或SSTR5（IC50为0.37 nM）具有优先亲和力的类似物对GH分泌的抑制作用相同（40 - 60%，P < 0.005），并且对SSTR2亲和力增强的化合物比兰瑞肽（EC50为2.30 nM）和SRIF（EC50为0.19 nM）更有效（GH抑制的EC50为0.05 - 0.09 nM）。同样，对SSTR2或SSTR5具有高亲和力的类似物可降低TSH分泌（30 - 40%，P < 0.005）。然而，仅优先结合SSTR2的化合物可有效抑制催乳素（20 - 30%，P < 0.05）。促黄体生成素可被SSTR2或SSTR5特异性类似物适度降低（15 - 20%）。一种SSTR5特异性类似物也仅抑制肢端肥大症肿瘤细胞中的GH。因此，原代人胎儿垂体细胞中SRIF对GH和TSH的调节由SSTR2和SSTR5介导，这两种受体在25周时均大量表达。相比之下，催乳素的抑制主要由SSTR2介导。这些结果表明SSTR5对GH和TSH的生理调节至关重要。因此，对该受体具有选择性亲和力的SRIF类似物在治疗分泌激素的垂体腺瘤方面可能更有效。
