title: Heterodimerization of apelin receptor and neurotensin receptor 1 induces phosphorylation of ERK(1/2) and cell proliferation via Gαq-mediated mechanism.
abstract: Dimerization of G protein-coupled receptors (GPCRs) is crucial for receptor function including agonist affinity, efficacy, trafficking and specificity of signal transduction, including G protein coupling. Emerging data suggest that the cardiovascular system is the main target of apelin, which exerts an overall neuroprotective role, and is a positive regulator of angiotensin-converting enzyme 2 (ACE2) in heart failure. Moreover, ACE2 cleaves off C-terminal residues of vasoactive peptides including apelin-13, and neurotensin that activate the apelin receptor (APJ) and neurotensin receptor 1 (NTSR1) respectively, that belong to the A class of GPCRs. Therefore, based on the similar mode of modification by ACE2 at peptide level, the homology at amino acid level and the capability of forming dimers with other GPCRs, we have been suggested that APJ and NTSR1 can form a functional heterodimer. Using co-immunoprecipitation, BRET and FRET, we provided conclusive evidence of heterodimerization between APJ and NTSR1 in a constitutive and induced form. Upon agonist stimulation, hetrodimerization enhanced ERK(1/2) activation and increased proliferation via activation of Gq α-subunits. These novel data provide evidence for a physiological role of APJ/NTSR1 heterodimers in terms of ERK(1/2) activation and increased intracellular calcium and induced cell proliferation and provide potential new pharmaceutical targets for cardiovascular disease.
authors.affiliation: Neurobiology Institute, Jining Medical University, Jining, Shandong, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Bai
authors.forename: Xin
authors.initials: X
authors.lastname: Cai
authors.forename: Yunlu
authors.initials: Y
authors.lastname: Jiang
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Karteris
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
mesh_terms: D000075244:Apelin Receptors; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D005434:Flow Cytometry; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D018613:Microscopy, Confocal; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D055503:Protein Multimerization; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018028:Receptors, Neurotensin / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: C104575:APLNR protein, human; D000075244:Apelin Receptors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; D018028:Receptors, Neurotensin; C114036:neurotensin type 1 receptor; 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: ERK
  1/2; G protein-coupled receptor; apelin receptor; heterodimerization; neurotensin receptor 1; resonance energy transfer