Smith R G, Pong S S, Hickey G, Jacks T, Cheng K, Leonard R, Cohen C J, Arena J P, Chang C H, Drisko J, Wyvratt M, Fisher M, Nargund R, Patchett A
Department of Biochemistry, Merck Research Laboratories, Rahway, New Jersey 07065, USA.
Recent Prog Horm Res. 1996;51:261-85; discussion 285-6.
Hormone replacement should provide a serum hormone profile similar to that found in normal physiology. This is generally impractical because hormones are usually released episodically and therefore require frequent administration. However, rather than replacing the hormone directly, in theory, one could administer a mimic or amplifier of the pulse generator that controls pulsatile release of the particular hormone. Using growth hormone (GH) as a paradigm we sought such a mimetic that would provide episodic GH release when administered by the oral route. A GH secretagogue MK0677, is described that has these ideal properties; following oral administration MK0677 amplifies episodic GH release. Mechanistically, it synergizes with growth hormone releasing hormone (GHRH) through a receptor and signal transduction pathway distinct from that of GHRH and is a functional antagonist of somatostatin (SRIF). MK0677 also acts on the arcuate nucleus and appears to stimulate GHRH release. By using 35S-MK0677, a new G-protein coupled receptor for MK0677 was characterized in the plasma membrane fraction of pituitary and hypothalamic tissue. The receptor is present in very low abundance and couples to phospholipase C. Other ligands selective for this receptor also cause synchronization of well-defined pathways leading to GH release. Repeated oral treatment of dogs once daily with MK0677 initiates amplified pulsatile GH release accompanied by increases in IGF-1 that are sustained. The unique biological properties of MK0677 and other synthetic ligands that bind to the same receptor force us to predict that these ligands mimic a naturally occurring hormone that regulates pulsatile GH release. Understanding the regulatory mechanisms involved in this paradigm has broad implications for the control of pulsatile rhythms in the endocrine system.
激素替代疗法应使血清激素水平与正常生理状态下的水平相似。但这通常不切实际，因为激素通常是间歇性释放的，因此需要频繁给药。然而，理论上，与其直接替代激素，不如给予一种模拟或增强控制特定激素脉冲式释放的脉冲发生器的物质。以生长激素（GH）为例，我们寻找一种口服给药时能引起GH间歇性释放的模拟物。一种生长激素促分泌素MK0677被描述具有这些理想特性；口服给药后，MK0677可增强GH的间歇性释放。从机制上讲，它通过一条不同于生长激素释放激素（GHRH）的受体和信号转导途径与GHRH协同作用，并且是生长抑素（SRIF）的功能性拮抗剂。MK0677还作用于弓状核，似乎能刺激GHRH的释放。通过使用35S-MK0677，在垂体和下丘脑组织的质膜部分鉴定出一种新的与MK0677结合的G蛋白偶联受体。该受体的丰度极低，并与磷脂酶C偶联。对该受体具有选择性的其他配体也会导致明确的导致GH释放的途径同步化。每天给狗口服一次MK0677进行重复治疗，可引发增强的脉冲式GH释放，并伴有胰岛素样生长因子-1（IGF-1）的持续增加。MK0677和其他与同一受体结合的合成配体的独特生物学特性使我们预测，这些配体模拟了一种调节脉冲式GH释放的天然激素。了解这一模式中涉及的调节机制对内分泌系统脉冲节律的控制具有广泛的意义。
