title: Human Neuropeptide S Receptor Is Activated via a Gαq Protein-biased Signaling Cascade by a Human Neuropeptide S Analog Lacking the C-terminal 10 Residues.
abstract: 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 Gαs- and Gαq-dependent signaling pathways. The human NPS analog hNPS-(1-10), lacking 10 residues from the C terminus, has been shown to stimulate Ca(2+)mobilization in a manner comparable with full-length hNPSin vitrobut seems to fail to induce biological activityin vivo Here, results derived from a number of cell-based functional assays, including intracellular cAMP-response element (CRE)-driven luciferase activity, Ca(2+)mobilization, and ERK1/2 phosphorylation, show that hNPS-(1-10) preferentially activates Gαq-dependent Ca(2+)mobilization while exhibiting less activity in triggering Gαs-dependent CRE-driven luciferase activity. We further demonstrate that both Gαq- and Gαs-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 Gαqinhibitor 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 Gαs-dependent signaling. In conclusion, our findings demonstrate that hNPS-(1-10) is a biased agonist favoring Gαq-dependent signaling. It may represent a valuable chemical probe for further investigation of the therapeutic potential of human NPS receptor-directed signalingin vivo.
authors: From the Institute of Biochemistry, College of Life Sciences, and.
authors: Yuan
authors: Y
authors: Liao
authors: From the Institute of Biochemistry, College of Life Sciences, and.
authors: Bin
authors: B
authors: Lu
authors: From the Institute of Biochemistry, College of Life Sciences, and.
authors: Qiang
authors: Q
authors: Ma
authors: the Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zijingang Campus, Zhejiang University, Hangzhou, Zhejiang 310058, China and.
authors: Gang
authors: G
authors: Wu
authors: From the Institute of Biochemistry, College of Life Sciences, and.
authors: Xiangru
authors: X
authors: Lai
authors: From the Institute of Biochemistry, College of Life Sciences, and.
authors: Jiashu
authors: J
authors: Zang
authors: From the Institute of Biochemistry, College of Life Sciences, and.
authors: Ying
authors: Y
authors: Shi
authors: the State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors: Dongxiang
authors: D
authors: Liu
authors: the Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zijingang Campus, Zhejiang University, Hangzhou, Zhejiang 310058, China and changhuahan@zju.edu.cn.
authors: Feng
authors: F
authors: Han
authors: From the Institute of Biochemistry, College of Life Sciences, and zhounaiming@zju.edu.cn.
authors: Naiming
authors: N
authors: Zhou
mesh_terms: D000595:Amino Acid Sequence; D020013:Calcium Signaling / Q000502:physiology*; D004789:Enzyme Activation / Q000502:physiology; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D017384:Sequence Deletion
chemical_list: C484532:NPSR1 protein, human; D009479:Neuropeptides; D043562:Receptors, G-Protein-Coupled; C506531:neuropeptide S, human; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D043802:GTP-Binding Protein alpha Subunits, Gq-G11
keywords: G protein; G protein-coupled receptor (GPCR); extracellular-signal-regulated kinase (ERK); neuropeptide; signal transduction