Murthy C K, Turner R J, Wong A O, Rao P D, Rivier J E, Peter R E
Department of Zoology, University of Alberta, Edmonton, Canada.
Neuroendocrinology. 1994 Jun;59(6):561-71. doi: 10.1159/000126706.
In goldfish the two native forms of gonadotropin-releasing hormone (GnRH), salmon GnRH (sGnRH) and chicken GnRH-II (cGnRH-II), stimulate both gonadotropin-II (GTH-II) and growth hormone (GH) release. Modifications of GnRH structure at positions 1, 2, 3, and 6 often result in an antagonist in goldfish, an observation well documented in mammalian studies. In a preliminary study in goldfish, a mammalian GnRH antagonist, [Ac-D(2)Nal1, 4Cl-D-Phe2, D(3)-Pal3,6, Arg5, D-Ala10]-mGnRH (analog L) weakly stimulated GTH-II release, and strongly inhibited GH release. The objectives of the present study were to study the dose-related actions of analog L on GTH-II and GH release in the goldfish, the specificity of inhibition of native GnRH actions, and to test whether analog L can act directly on goldfish pituitary cells. In a goldfish pituitary fragments perifusion system, analog L at different concentrations, given as 2-min pulses or as 30-min prolonged treatments, stimulated GTH-II and inhibited GH release in a dose-dependent manner. Analog L at 2 microM concentration (45 min) significantly suppressed sGnRH- and cGnRH-II-stimulated GTH-II as well as GH release. Analog L specifically inhibited GnRH-stimulated GH release, without having any significant effects on the GH release induced by either SKF38393, a dopamine D1 receptor agonist, or thyrotropin-releasing hormone. The GTH-II stimulatory and GH-inhibitory actions of analog L were significantly suppressed by a 'true' GnRH antagonist (Ac-delta 3-Pro1, 4FD-Phe2, D-Trp3,6)-mGnRH. Further, analog L stimulated GTH-II release and suppressed GH release from the enzymatically dispersed goldfish pituitary cells, indicating the direct actions of analog L at the pituitary cell level. Analog L also displaced 125I-(D-Arg6, Pro9 NHEt)-sGnRH bound to crude goldfish pituitary membrane preparations in a dose-related manner. In conclusion, contrary to its action as a potent GnRH antagonist in mammals, analog L has GTH-II stimulatory action in goldfish. Analog L by acting via GnRH receptors at the pituitary cell level differentially acts on GTH-II and GH release, suggesting functional differences in the properties of the GnRH receptors on GTH and GH cells. Analog L also specifically inhibits sGnRH and cGnRH-II actions on GTH-II and GH release.
在金鱼中，两种天然形式的促性腺激素释放激素（GnRH），即鲑鱼GnRH（sGnRH）和鸡GnRH-II（cGnRH-II），均可刺激促性腺激素-II（GTH-II）和生长激素（GH）的释放。在第1、2、3和6位对GnRH结构进行修饰，在金鱼中通常会产生拮抗剂，这一观察结果在哺乳动物研究中已有充分记载。在一项针对金鱼的初步研究中，一种哺乳动物GnRH拮抗剂，[Ac-D(2)Nal1, 4Cl-D-Phe2, D(3)-Pal3,6, Arg5, D-Ala10]-mGnRH（类似物L）对GTH-II的释放有微弱刺激作用，而对GH的释放有强烈抑制作用。本研究的目的是研究类似物L对金鱼GTH-II和GH释放的剂量相关作用、对天然GnRH作用抑制的特异性，并测试类似物L是否能直接作用于金鱼垂体细胞。在金鱼垂体碎片灌流系统中，以2分钟脉冲或30分钟延长处理的方式给予不同浓度的类似物L，其以剂量依赖的方式刺激GTH-II释放并抑制GH释放。2 microM浓度的类似物L（45分钟）可显著抑制sGnRH和cGnRH-II刺激的GTH-II以及GH释放。类似物L特异性抑制GnRH刺激的GH释放，而对多巴胺D1受体激动剂SKF38393或促甲状腺激素释放激素诱导的GH释放无任何显著影响。类似物L对GTH-II的刺激作用和对GH的抑制作用被一种“真正的”GnRH拮抗剂（Ac-delta 3-Pro1, 4FD-Phe2, D-Trp3,6）-mGnRH显著抑制。此外，类似物L刺激了酶分散的金鱼垂体细胞释放GTH-II并抑制了GH释放，表明类似物L在垂体细胞水平具有直接作用。类似物L还以剂量相关的方式取代了与金鱼垂体粗膜制剂结合的125I-(D-Arg6, Pro9 NHEt)-sGnRH。总之，与它在哺乳动物中作为强效GnRH拮抗剂的作用相反，类似物L在金鱼中具有刺激GTH-II释放的作用。类似物L通过在垂体细胞水平作用于GnRH受体，对GTH-II和GH释放产生不同作用，这表明GTH和GH细胞上GnRH受体特性存在功能差异。类似物L还特异性抑制sGnRH和cGnRH-II对GTH-II和GH释放的作用。
