Structure-activity studies on neuropeptide S -: Identification of the amino acid residues crucial for receptor activation
Structure-activity studies on neuropeptide S -: Identification of the amino acid residues crucial for receptor activation
复制标题
DOI：
10.1074/jbc.m601846200
复制
发表时间：
2006-07-28
影响因子：
4.8
通讯作者：
Guerrini, Remo
中科院分区：
文献类型：
--
作者：
Roth, Adelheid L.;Marzola, Erika;Guerrini, Remo
神经肽S被认为是以前的孤儿G蛋白偶联受体GPR154的内源性配体，现在被称为神经肽受体(NPSR)。NPS-NPSR受体系统调节重要的生物学功能，如睡眠/觉醒、运动、焦虑和食物摄入。为了收集有关NPS与其受体相互作用机制的信息，进行了经典的构效关系研究。通过ALA和D-SCAN以及N-端和C-端截断获得的人(H)NPS衍生物被评估它们在表达人重组NPSR的HEK293细胞中刺激钙释放的能力。本研究的结果表明：(I)hNPS(1-10)片段模拟hNPS的作用；(Ii)Phe(2)、Arg(3)和Asn(4)是生物活性的关键；(Iii)Thr(8)-Gly(9)-Met(10)序列对受体激活是重要的，尽管没有严格的化学要求；(Iv)Val(6)-Gly(7)序列是上述两个结构域之间的铰链区。然而，hNPS-(1-10)不能完全模拟侧脑室注射hNPS对小鼠运动活动的刺激作用，这表明该肽的C末端区域对体内活动仍然重要。综上所述，本研究确定了该肽中对受体激活最重要的氨基酸残基。
Neuropeptide S ( NPS) has been recently recognized as the endogenous ligand for the previous orphan G-protein-coupled receptor GPR154, now referred to as the NPS receptor ( NPSR). The NPS-NPSR receptor system regulates important biological functions such as sleeping/wakening, locomotion, anxiety, and food intake. To collect information on the mechanisms of interaction between NPS and its receptor, a classical structure-activity relationship study was performed. Human ( h) NPS derivatives obtained by Ala and D-scan and N- and C-terminal truncation were assessed for their ability to stimulate calcium release in HEK293 cells expressing the human recombinant NPSR. The results of this study indicate that ( i) the effect of hNPS is mimicked by the fragment hNPS( 1 - 10); ( ii) Phe(2), Arg(3), and Asn(4) are crucial for biological activity; ( iii) the sequence Thr(8)-Gly(9)-Met(10) is important for receptor activation, although with non-stringent chemical requirements; and ( iv) the sequence Val(6)-Gly(7) acts as a hinge region between the two above-mentioned domains. However, the stimulatory effect of hNPS given intracerebroventricularly on mouse locomotor activity was not fully mimicked by hNPS-( 1 - 10), suggesting that the C-terminal region of the peptide maintains importance for in vivo activity. In conclusion, this study identified the amino acid residues of this peptide most important for receptor activation.