Luque R M, Peinado J R, Gracia-Navarro F, Broglio F, Ghigo E, Kineman R D, Malagón M M, Castaño J P
Department of Cell Biology, Physiology and Immunology, University of Córdoba, Campus de Rabanales, Edificio C-6, Planta 3, E-14014 Córdoba, Spain.
J Mol Endocrinol. 2006 Jun;36(3):547-56. doi: 10.1677/jme.1.01980.
Cortistatin is a recently discovered neuropeptide that is structurally related to somatostatin, the classic inhibitor of growth hormone (GH) release. Cortistatin binds with high affinity to all five somatostatin receptors (sst1-5), and, like somatostatin, cortistatin inhibits in vivo GH release in man and rats. In this report, we compared the in vitro actions of cortistatin and somatostatin using primary pig pituitary cell cultures. In this species, we have previously reported that somatostatin not only inhibits GH-releasing hormone (GHRH)-stimulated GH release at high doses, but also stimulates basal GH release at low (pM) doses, a dual response that is markedly dependent on the subpopulation of pituitary somatotropes examined. Results reported herein demonstrate that cortistatin closely mimics the dose-dependent inhibitory and stimulatory effects of somatostatin on GH secretion. As cortistatin, unlike somatostatin, binds to the human receptor for ghrelin/GH secretagogs (GHS-R), we also investigated whether cortistatin stimulates GH release through this receptor by using a synthetic, short form of cortistatin, cortistatin-8 (CST8), which lacks the sst-binding capacity of full-length cortistatin but retains its GHS-R-binding capacity. Interestingly, CST8 stimulated GH release only at low doses (10(-15) M), and did not reduce GH secretion stimulated by GHRH, ghrelin, or low-dose, full-length cortistatin, yet it counteracted that induced by a nonpeptidyl GHS, L-163 255. Taken together, our results indicate that the dual, inhibitory and stimulatory effects of cortistatin on GH release closely parallel those of somatostatin and are probably mediated by the same receptor(s) and signaling pathway(s) for both peptides. Furthermore, they suggest that the pathway(s) activated by cortistatin (and somatostatin) to stimulate GH release are not initiated by GHS-R activation.
可体他汀是一种最近发现的神经肽，在结构上与生长激素（GH）释放的经典抑制剂生长抑素相关。可体他汀与所有五种生长抑素受体（sst1 - 5）具有高亲和力结合，并且与生长抑素一样，可体他汀在体内抑制人和大鼠的GH释放。在本报告中，我们使用原代猪垂体细胞培养物比较了可体他汀和生长抑素的体外作用。在这个物种中，我们之前曾报道生长抑素不仅在高剂量时抑制生长激素释放激素（GHRH）刺激的GH释放，而且在低（皮摩尔）剂量时刺激基础GH释放，这种双重反应明显取决于所检测的垂体生长激素细胞亚群。本文报道的结果表明，可体他汀紧密模拟生长抑素对GH分泌的剂量依赖性抑制和刺激作用。由于可体他汀与生长抑素不同，它能与人胃饥饿素/生长激素促分泌素受体（GHS - R）结合，我们还研究了可体他汀是否通过该受体刺激GH释放，方法是使用一种合成的、短形式的可体他汀，即可体他汀 - 8（CST8），它缺乏全长可体他汀的sst结合能力，但保留了其GHS - R结合能力。有趣的是，CST8仅在低剂量（10^(-15) M）时刺激GH释放，并且不降低由GHRH、胃饥饿素或低剂量全长可体他汀刺激的GH分泌，但它能抵消由非肽类生长激素促分泌素L - 163 255诱导的GH分泌。综上所述，我们的结果表明，可体他汀对GH释放的双重抑制和刺激作用与生长抑素的作用密切平行，并且可能由两种肽的相同受体和信号通路介导。此外，它们表明可体他汀（和生长抑素）激活以刺激GH释放的信号通路不是由GHS - R激活引发的。
