Human Neuropeptide S Receptor Is Activated via a G alpha(q) Protein-biased Signaling Cascade by a Human Neuropeptide S Analog Lacking the C-terminal 10 Residues

doi:10.1074/jbc.M115.704122

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	Human Neuropeptide S Receptor Is Activated via a G alpha(q) Protein-biased Signaling Cascade by a Human Neuropeptide S Analog Lacking the C-terminal 10 Residues
	Liao, Yuan 2; Lu, Bin 2; Ma, Qiang 2; Wu, Gang 3; Lai, Xiangru 2; Zang, Jiashu 2; Shi, Ying 2; Liu, Dongxiang1 ; Han, Feng 3; Zhou, Naiming 2
刊名	JOURNAL OF BIOLOGICAL CHEMISTRY
	2016-04-01
卷号	291 期号:14 页码:7505-7516
ISSN号	0021-9258
DOI	10.1074/jbc.M115.704122
文献子类	Article
英文摘要	Human neuropeptide S (NPS) and its cognate receptor regulate important biological functions in the brain and have emerged as a future therapeutic target for treatment of a variety of neurological and psychiatric diseases. The human NPS (hNPS) receptor has been shown to dually couple to G alpha(s)- and G alpha(q)-dependent signaling pathways. The human NPS analog hNPS-(1-10), lacking 10 residues from the C terminus, has been shown to stimulate Ca2+ mobilization in a manner comparable with full-length hNPS in vitro but seems to fail to induce biological activity in vivo. Here, results derived from a number of cell-based functional assays, including intracellular cAMP-response element (CRE)-driven luciferase activity, Ca2+ mobilization, and ERK1/2 phosphorylation, show that hNPS-(1-10) preferentially activates G alpha(q)-dependent Ca2+ mobilization while exhibiting less activity in triggering G alpha(s)-dependent CRE-driven luciferase activity. We further demonstrate that both G alpha(q)- and G alpha(s)-coupled signaling pathways contribute to full-length hNPS-mediated activation of ERK1/2, whereas hNPS-(1-10)promoted ERK1/2 activation is completely inhibited by the G alpha(q) inhibitor UBO-QIC but not by the PKA inhibitor H89. Moreover, the results of Ala-scanning mutagenesis of hNPS-(1-13) indicated that residues Lys(11) and Lys(12) are structurally crucial for the hNPS receptor to couple to G alpha(s)-dependent signaling. In conclusion, our findings demonstrate that hNPS-(1-10) is a biased agonist favoring G alpha(q)-dependent signaling. It may represent a valuable chemical probe for further investigation of the therapeutic potential of human NPS receptor-directed signaling in vivo.
资助项目	Ministry of Science and Technology of China[2012CB910402] ; Ministry of Science and Technology of China[2012AA020303] ; National Natural Science Foundation of China[81173106] ; National Natural Science Foundation of China[31200621]
WOS关键词	FUNCTIONAL SELECTIVITY ; SENSING RECEPTOR ; FOOD-INTAKE ; IDENTIFICATION ; AGONISTS ; PHARMACOLOGY ; PEPTIDE ; MICE ; RATS ; DELINEATION
WOS研究方向	Biochemistry & Molecular Biology
语种	英语
出版者	AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
WOS记录号	WOS:000383447600025
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276082]
专题	药理学第三研究室中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Han, Feng; Zhou, Naiming
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 2.Zhejiang Univ, Coll Life Sci, Inst Biochem, Zijingang Campus, Hangzhou 310058, Zhejiang, Peoples R China; 3.Zhejiang Univ, Coll Pharmaceut Sci, Inst Pharmacol & Toxicol, Zijingang Campus, Hangzhou 310058, Zhejiang, Peoples R China;
推荐引用方式 GB/T 7714	Liao, Yuan,Lu, Bin,Ma, Qiang,et al. Human Neuropeptide S Receptor Is Activated via a G alpha(q) Protein-biased Signaling Cascade by a Human Neuropeptide S Analog Lacking the C-terminal 10 Residues[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2016,291(14):7505-7516.
APA	Liao, Yuan.,Lu, Bin.,Ma, Qiang.,Wu, Gang.,Lai, Xiangru.,...&Zhou, Naiming.(2016).Human Neuropeptide S Receptor Is Activated via a G alpha(q) Protein-biased Signaling Cascade by a Human Neuropeptide S Analog Lacking the C-terminal 10 Residues.JOURNAL OF BIOLOGICAL CHEMISTRY,291(14),7505-7516.
MLA	Liao, Yuan,et al."Human Neuropeptide S Receptor Is Activated via a G alpha(q) Protein-biased Signaling Cascade by a Human Neuropeptide S Analog Lacking the C-terminal 10 Residues".JOURNAL OF BIOLOGICAL CHEMISTRY 291.14(2016):7505-7516.