Kojima Masayasu, Hosoda Hiroshi, Kangawa Kenji
Molecular Genetics, Institute of Life Science, Kurume University, Kurume, Fukuoka, Japan.
Methods Enzymol. 2012;514:45-61. doi: 10.1016/B978-0-12-381272-8.00003-9.
Small synthetic molecules called growth hormone secretagogues (GHSs) stimulate the release of growth hormone (GH) from the pituitary. They act through the GHS-R, a G-protein-coupled receptor highly expressed in the hypothalamus and pituitary. Using an orphan receptor strategy with a stable cell line expressing GHS-R, we purified endogenous ligands for GHS-R from rat and human stomach and named it "ghrelin," after a word root (ghre) in Proto-Indo-European languages meaning "grow." Ghrelin is a peptide hormone in which the third amino acid, usually a serine but in some species a threonine, is modified by a fatty acid; this modification is essential for ghrelin's activity. The main active form of rat ghrelin is 28-amino acid peptides with n-octanoyl modification. In rat stomach, a second type of ghrelin peptide was purified, identified as des-Gln14-ghrelin. With the exception of the deletion of Gln14, des-Gln14-ghrelin is identical to ghrelin, retaining the n-octanoic acid modification. Des-Gln14-ghrelin is encoded by an mRNA created by alternative splicing of the ghrelin gene. As in the rat, the major active form of human ghrelin is a 28-amino acid peptide with an n-octanoylated Ser3. However, in human stomach, several minor forms of human ghrelin peptides have been isolated. These can be classified into four groups by the type of acylation observed at Ser3 and into two groups by the amino acids in length. The discovery of ghrelin indicates that the release of GH from the pituitary and appetite stimulation might be regulated by ghrelin derived from the stomach.
一类名为生长激素促分泌素（GHSs）的小分子合成物质可刺激垂体释放生长激素（GH）。它们通过生长激素促分泌素受体（GHS-R）发挥作用，该受体是一种G蛋白偶联受体，在下丘脑和垂体中高度表达。我们利用一种孤儿受体策略，借助一个稳定表达GHS-R的细胞系，从大鼠和人类胃中纯化出了GHS-R的内源性配体，并根据原始印欧语系中一个意为“生长”的词根（ghre），将其命名为“胃饥饿素”。胃饥饿素是一种肽类激素，其第三个氨基酸（通常为丝氨酸，但在某些物种中为苏氨酸）会被脂肪酸修饰；这种修饰对于胃饥饿素的活性至关重要。大鼠胃饥饿素的主要活性形式是具有正辛酰基修饰的28个氨基酸的肽段。在大鼠胃中，还纯化出了第二种类型的胃饥饿素肽段，鉴定为去谷氨酰胺14-胃饥饿素。除了缺失谷氨酰胺14外，去谷氨酰胺14-胃饥饿素与胃饥饿素相同，保留了正辛酸修饰。去谷氨酰胺14-胃饥饿素由胃饥饿素基因选择性剪接产生的mRNA编码。与大鼠一样，人类胃饥饿素的主要活性形式也是一种具有正辛酰化丝氨酸3的28个氨基酸的肽段。然而，在人类胃中，已分离出几种人类胃饥饿素肽段的次要形式。这些肽段可根据丝氨酸3处观察到的酰化类型分为四类，根据长度的氨基酸分为两类。胃饥饿素的发现表明，垂体释放生长激素和刺激食欲可能受源自胃的胃饥饿素调节。
